KLF4: Difference between revisions

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'''Kruppel-like factor 4''' (KLF4; gut-enriched Krüppel-like factor or GKLF) is a zinc-finger transcription factor, and it was first identified in 1996.<ref name="pmid8702718">{{cite journal | vauthors = Shields JM, Christy RJ, Yang VW | title = Identification and characterization of a gene encoding a gut-enriched Krüppel-like factor expressed during growth arrest | journal = The Journal of Biological Chemistry | volume = 271 | issue = 33 | pages = 20009–17 | date = August 1996 | pmid = 8702718 }}</ref> KLF4 is a member of the KLF [[Family (biology)|family]] of [[transcription factors]], which belongs to the relatively large family of SP1-like transcription factors.<ref>{{cite journal | vauthors = Black AR, Black JD, Azizkhan-Clifford J | title = Sp1 and krüppel-like factor family of transcription factors in cell growth regulation and cancer | journal = Journal of Cellular Physiology | volume = 188 | issue = 2 | pages = 143–60 | date = August 2001 | pmid = 11424081 | doi = 10.1002/jcp.1111 }}</ref><ref name="pmid11137451">{{cite journal | vauthors = Dang DT, Pevsner J, Yang VW | title = The biology of the mammalian Krüppel-like family of transcription factors | journal = The International Journal of Biochemistry & Cell Biology | volume = 32 | issue = 11-12 | pages = 1103–21 | date = November 2000 | pmid = 11137451 }}</ref><ref>{{cite journal | vauthors = Kaczynski J, Cook T, Urrutia R | title = Sp1- and Krüppel-like transcription factors | journal = Genome Biology | volume = 4 | issue = 2 | pages = 206 | year = 2003 | pmid = 12620113 }}</ref> KLF4 is involved in the regulation of [[Cell proliferation|proliferation]], [[Cellular differentiation|differentiation]], [[apoptosis]] and [[somatic cell]] reprogramming. Evidence also suggests that KLF4 is a [[tumor]] suppressor in certain [[cancers]], including [[Colorectal cancer]].<ref>{{cite journal | vauthors = El-Karim EA, Hagos EG, Ghaleb AM, Yu B, Yang VW | title = Krüppel-like factor 4 regulates genetic stability in mouse embryonic fibroblasts | journal = Molecular Cancer | volume = 12 | pages = 89 | date = August 2013 | pmid =  | doi = 10.1186/1476-4598-12-89 | url = http://www.molecular-cancer.com/content/12/1/89 }}</ref> It has three C2H2-zinc fingers at its carboxyl terminus that are closely related to another KLF, [[KLF2]].<ref name="pmid11137451" /> It has two nuclear localization sequences that signals it to localize to the nucleus.<ref>{{cite journal | vauthors = Shields JM, Yang VW | title = Two potent nuclear localization signals in the gut-enriched Krüppel-like factor define a subfamily of closely related Krüppel proteins | journal = The Journal of Biological Chemistry | volume = 272 | issue = 29 | pages = 18504–7 | date = July 1997 | pmid = 9218496 }}</ref> In [[embryonic stem cells]] (ESCs), KLF4 has been demonstrated to be a good indicator of stem-like capacity. It is suggested that the same is true in [[mesenchymal stem cells]] (MSCs).
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In humans, the [[protein]] is 513 amino acids with a predicted molecular weight of approximately 55kDa and is encoded by the ''KLF4'' [[gene]].<ref>{{cite web | title = Entrez Gene: KLF4 Kruppel-like factor 4 (gut)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9314| accessdate = }}</ref>. The KLF4 gene is conserved in chimpanzee, [[rhesus monkey]], dog, cow, mouse, rat, chicken, [[zebrafish]], and frog.<ref>{{Cite web|url = https://www.ncbi.nlm.nih.gov/gene/9314|title = Kruppel-like factor 4|date = |accessdate = |website = |publisher = }}</ref>
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== Interactions ==
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KLF4 can activate transcription by interacting via it N-terminus with specific transcriptional co-activators, such as [[p300-CBP coactivator family]].<ref>{{cite journal | vauthors = Garrett-Sinha LA, Eberspaecher H, Seldin MF, de Crombrugghe B | title = A gene for a novel zinc-finger protein expressed in differentiated epithelial cells and transiently in certain mesenchymal cells | journal = The Journal of Biological Chemistry | volume = 271 | issue = 49 | pages = 31384–90 | date = December 1996 | pmid = 8940147 }}</ref><ref>{{cite journal | vauthors = Geiman DE, Ton-That H, Johnson JM, Yang VW | title = Transactivation and growth suppression by the gut-enriched Krüppel-like factor (Krüppel-like factor 4) are dependent on acidic amino acid residues and protein-protein interaction | journal = Nucleic Acids Research | volume = 28 | issue = 5 | pages = 1106–13 | date = March 2000 | pmid = 10666450 }}</ref><ref>{{cite journal | vauthors = Evans PM, Zhang W, Chen X, Yang J, Bhakat KK, Liu C | title = Kruppel-like factor 4 is acetylated by p300 and regulates gene transcription via modulation of histone acetylation | journal = The Journal of Biological Chemistry | volume = 282 | issue = 47 | pages = 33994–4002 | date = November 2007 | pmid = 17908689 | doi = 10.1074/jbc.M701847200 }}</ref> Transcriptional repression by KLF4 is carried out by KLF4 competing with an activator for binding to a target DNA sequence (9-12).<ref>{{cite journal | vauthors = Zhang W, Shields JM, Sogawa K, Fujii-Kuriyama Y, Yang VW | title = The gut-enriched Krüppel-like factor suppresses the activity of the CYP1A1 promoter in an Sp1-dependent fashion | journal = The Journal of Biological Chemistry | volume = 273 | issue = 28 | pages = 17917–25 | date = July 1998 | pmid = 9651398 }}</ref><ref>{{cite journal | vauthors = Ai W, Liu Y, Langlois M, Wang TC | title = Kruppel-like factor 4 (KLF4) represses histidine decarboxylase gene expression through an upstream Sp1 site and downstream gastrin responsive elements | journal = The Journal of Biological Chemistry | volume = 279 | issue = 10 | pages = 8684–93 | date = March 2004 | pmid = 14670968 | doi = 10.1074/jbc.M308278200 }}</ref><ref>{{cite journal | vauthors = Feinberg MW, Cao Z, Wara AK, Lebedeva MA, Senbanerjee S, Jain MK | title = Kruppel-like factor 4 is a mediator of proinflammatory signaling in macrophages | journal = The Journal of Biological Chemistry | volume = 280 | issue = 46 | pages = 38247–58 | date = November 2005 | pmid = 16169848 | doi = 10.1074/jbc.M509378200 }}</ref><ref>{{cite journal | vauthors = Kanai M, Wei D, Li Q, Jia Z, Ajani J, Le X, Yao J, Xie K | title = Loss of Krüppel-like factor 4 expression contributes to Sp1 overexpression and human gastric cancer development and progression | journal = Clinical Cancer Research | volume = 12 | issue = 21 | pages = 6395–402 | date = November 2006 | pmid = 17085651 | doi = 10.1158/1078-0432.CCR-06-1034 }}</ref> KLF4 has been shown to [[Protein-protein interaction|interact]] with [[CREB-binding protein]].<ref name="pmid10666450">{{cite journal | vauthors = Geiman DE, Ton-That H, Johnson JM, Yang VW | title = Transactivation and growth suppression by the gut-enriched Krüppel-like factor (Krüppel-like factor 4) are dependent on acidic amino acid residues and protein-protein interaction | journal = Nucleic Acids Research | volume = 28 | issue = 5 | pages = 1106–13 | date = March 2000 | pmid = 10666450 | pmc = 102607 | doi = 10.1093/nar/28.5.1106 }}</ref>
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It was found that the transcription factor Klf4 present at the promoter of an enzymatic subunit of [[telomerase]] ([[Telomerase reverse transcriptase|TERT]]), where it formed a complex with [[Beta-catenin|
β-catenin]]. Klf4 was required for accumulation of β-catenin at the Tert promoter but was unable to stimulate Tert expression in the absence of β-catenin.<ref name="pmid22723415">{{cite journal | vauthors = Hoffmeyer K, Raggioli A, Rudloff S, Anton R, Hierholzer A, Del Valle I, Hein K, Vogt R, Kemler R | title = Wnt/β-catenin signaling regulates telomerase in stem cells and cancer cells | journal = Science | volume = 336 | issue = 6088 | pages = 1549–54 | date = June 2012 | pmid = 22723415 | doi = 10.1126/science.1218370 }}</ref>
 
== Function ==
KLF4 has diverse functions, and has been garnering attention in recent years because some of its functions are apparently contradicting, but mainly since the discovery of its integral role as one of four key factors that are essential for inducing pluripotent stem cells.<ref>{{cite journal | vauthors = Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S | title = Induction of pluripotent stem cells from adult human fibroblasts by defined factors | journal = Cell | volume = 131 | issue = 5 | pages = 861–72 | date = November 2007 | pmid = 18035408 | doi = 10.1016/j.cell.2007.11.019 }}</ref><ref>{{cite journal | vauthors = Takahashi K, Yamanaka S | title = Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors | journal = Cell | volume = 126 | issue = 4 | pages = 663–76 | date = August 2006 | pmid = 16904174 | doi = 10.1016/j.cell.2006.07.024 }}</ref> KLF4 is highly expressed in non-dividing cells and its overexpression induces cell cycle arrest.<ref name="pmid8702718" /><ref name="pmid11390382">{{cite journal | vauthors = Chen X, Johns DC, Geiman DE, Marban E, Dang DT, Hamlin G, Sun R, Yang VW | title = Krüppel-like factor 4 (gut-enriched Krüppel-like factor) inhibits cell proliferation by blocking G1/S progression of the cell cycle | journal = The Journal of Biological Chemistry | volume = 276 | issue = 32 | pages = 30423–8 | date = August 2001 | pmid = 11390382 | doi = 10.1074/jbc.M101194200 }}</ref><ref>{{cite journal | vauthors = Dang DT, Chen X, Feng J, Torbenson M, Dang LH, Yang VW | title = Overexpression of Krüppel-like factor 4 in the human colon cancer cell line RKO leads to reduced tumorigenecity | journal = Oncogene | volume = 22 | issue = 22 | pages = 3424–30 | date = May 2003 | pmid = 12776194 | doi = 10.1038/sj.onc.1206413 }}</ref><ref name="pmid14627709">{{cite journal | vauthors = Yoon HS, Yang VW | title = Requirement of Krüppel-like factor 4 in preventing entry into mitosis following DNA damage | journal = The Journal of Biological Chemistry | volume = 279 | issue = 6 | pages = 5035–41 | date = February 2004 | pmid = 14627709 | doi = 10.1074/jbc.M307631200 }}</ref><ref name="pmid12427745">{{cite journal | vauthors = Yoon HS, Chen X, Yang VW | title = Kruppel-like factor 4 mediates p53-dependent G1/S cell cycle arrest in response to DNA damage | journal = The Journal of Biological Chemistry | volume = 278 | issue = 4 | pages = 2101–5 | date = January 2003 | pmid = 12427745 | doi = 10.1074/jbc.M211027200 }}</ref> KLF4 is particularly important in preventing cell division when the DNA is damaged.<ref name="pmid11390382" /><ref name="pmid14627709" /><ref name="pmid12427745"/><ref>{{cite journal | vauthors = Yoon HS, Ghaleb AM, Nandan MO, Hisamuddin IM, Dalton WB, Yang VW | title = Krüppel-like factor 4 prevents centrosome amplification following gamma-irradiation-induced DNA damage | journal = Oncogene | volume = 24 | issue = 25 | pages = 4017–25 | date = June 2005 | pmid = 15806166 | doi = 10.1038/sj.onc.1208576 }}</ref> KLF4 is also important in regulating centrosome number and chromosome number (genetic stability),<ref>{{cite journal | vauthors = El-Karim EA, Hagos EG, Ghaleb AM, Yu B, Yang VW | title = Krüppel-like factor 4 regulates genetic stability in mouse embryonic fibroblasts | journal = Molecular Cancer | volume = 12 | pages = 89 | date = August 2013 | pmid = 23919723 | doi = 10.1186/1476-4598-12-89 }}</ref><ref>{{cite journal | vauthors = Hagos EG, Ghaleb AM, Dalton WB, Bialkowska AB, Yang VW | title = Mouse embryonic fibroblasts null for the Krüppel-like factor 4 gene are genetically unstable | journal = Oncogene | volume = 28 | issue = 9 | pages = 1197–205 | date = March 2009 | pmid = 19137014 | doi = 10.1038/onc.2008.465 }}</ref><ref>{{cite journal | vauthors = Ghaleb AM, Elkarim EA, Bialkowska AB, Yang VW | title = KLF4 Suppresses Tumor Formation in Genetic and Pharmacological Mouse Models of Colonic Tumorigenesis | journal = Molecular Cancer Research | volume = 14 | issue = 4 | pages = 385–96 | date = April 2016 | pmid = 26839262 | doi = 10.1158/1541-7786.MCR-15-0410 }}</ref> and in promoting cell survival. <ref>{{cite journal | vauthors = Rowland BD, Bernards R, Peeper DS | title = The KLF4 tumour suppressor is a transcriptional repressor of p53 that acts as a context-dependent oncogene | journal = Nature Cell Biology | volume = 7 | issue = 11 | pages = 1074–82 | date = November 2005 | pmid = 16244670 | doi = 10.1038/ncb1314 }}</ref><ref>{{cite journal | vauthors = Yang Y, Goldstein BG, Chao HH, Katz JP | title = KLF4 and KLF5 regulate proliferation, apoptosis and invasion in esophageal cancer cells | journal = Cancer Biology & Therapy | volume = 4 | issue = 11 | pages = 1216–21 | date = November 2005 | pmid = 16357509 }}</ref><ref>{{cite journal | vauthors = McConnell BB, Ghaleb AM, Nandan MO, Yang VW | title = The diverse functions of Krüppel-like factors 4 and 5 in epithelial biology and pathobiology | journal = BioEssays | volume = 29 | issue = 6 | pages = 549–57 | date = June 2007 | pmid = 17508399 | doi = 10.1002/bies.20581 }}</ref><ref>{{cite journal | vauthors = Talmasov D, Xinjun Z, Yu B, Nandan MO, Bialkowska AB, Elkarim E, Kuruvilla J, Yang VW, Ghaleb AM | title = Krüppel-like factor 4 is a radioprotective factor for the intestine following γ-radiation-induced gut injury in mice | journal = American Journal of Physiology. Gastrointestinal and Liver Physiology | volume = 308 | issue = 2 | pages = G121-38 | date = January 2015 | pmid = 25414097 | doi = 10.1152/ajpgi.00080.2014 }}</ref><ref name="pmid25834779">{{cite journal | vauthors = Wang B, Zhao MZ, Cui NP, Lin DD, Zhang AY, Qin Y, Liu CY, Yan WT, Shi JH, Chen BP | title = Krüppel-like factor 4 induces apoptosis and inhibits tumorigenic progression in SK-BR-3 breast cancer cells | journal = FEBS Open Bio | volume = 5 | pages = 147–54 | date = 2 March 2015 | pmid = 25834779 | doi = 10.1016/j.fob.2015.02.003 }}</ref><ref>{{cite journal | vauthors = Kuruvilla JG, Kim CK, Ghaleb AM, Bialkowska AB, Kuo CJ, Yang VW | title = Krüppel-like Factor 4 Modulates Development of BMI1(+) Intestinal Stem Cell-Derived Lineage Following γ-Radiation-Induced Gut Injury in Mice | journal = Stem Cell Reports | volume = 6 | issue = 6 | pages = 815–24 | date = June 2016 | pmid = 27237377 | doi = 10.1016/j.stemcr.2016.04.014 }}</ref> However, some studies have revealed that under certain conditions KLF4 may switch its role from pro-cell survival to pro-cell death.<ref name="pmid25834779" /><ref>{{cite journal | vauthors = Liu MD, Liu Y, Liu JW, Zhang HL, Xiao XZ | title = [Effect of Krüppel-like factor 4 overexpression on heat stress-induced apoptosis of Raw264.7 macrophages] | journal = Zhong Nan Da Xue Xue Bao. Yi Xue Ban = Journal of Central South University. Medical Sciences | volume = 32 | issue = 6 | pages = 1002–6 | date = December 2007 | pmid = 18182717 }}</ref><ref>{{cite journal | vauthors = Li Z, Zhao J, Li Q, Yang W, Song Q, Li W, Liu J | title = KLF4 promotes hydrogen-peroxide-induced apoptosis of chronic myeloid leukemia cells involving the bcl-2/bax pathway | journal = Cell Stress & Chaperones | volume = 15 | issue = 6 | pages = 905–12 | date = November 2010 | pmid = 20401760 | doi = 10.1007/s12192-010-0199-5 }}</ref><ref>{{cite journal | vauthors = Whitlock NC, Bahn JH, Lee SH, Eling TE, Baek SJ | title = Resveratrol-induced apoptosis is mediated by early growth response-1, Krüppel-like factor 4, and activating transcription factor 3 | journal = Cancer Prevention Research | volume = 4 | issue = 1 | pages = 116–27 | date = January 2011 | pmid = 21205742 | doi = 10.1158/1940-6207.CAPR-10-0218 }}</ref>
 
KLF4 is expressed in the cells that are non-dividing and are terminally differentiated in the [[intestinal epithelium]], where KLF4 is important in the regulation of intestinal epithelium homeostasis (terminal cell differentiation and proper localization of the different intestinal epithelium cell types).<ref>{{cite journal | vauthors = Katz JP, Perreault N, Goldstein BG, Lee CS, Labosky PA, Yang VW, Kaestner KH | title = The zinc-finger transcription factor Klf4 is required for terminal differentiation of goblet cells in the colon | journal = Development | volume = 129 | issue = 11 | pages = 2619–28 | date = June 2002 | pmid = 12015290 }}</ref><ref>{{cite journal | vauthors = Choi BJ, Cho YG, Song JW, Kim CJ, Kim SY, Nam SW, Yoo NJ, Lee JY, Park WS | title = Altered expression of the KLF4 in colorectal cancers | journal = Pathology, Research and Practice | volume = 202 | issue = 8 | pages = 585–9 | date = 2006 | pmid = 16814484 | doi = 10.1016/j.prp.2006.05.001 }}</ref><ref>{{cite journal | vauthors = Ghaleb AM, McConnell BB, Nandan MO, Katz JP, Kaestner KH, Yang VW | title = Haploinsufficiency of Krüppel-like factor 4 promotes adenomatous polyposis coli dependent intestinal tumorigenesis | journal = Cancer Research | volume = 67 | issue = 15 | pages = 7147–54 | date = August 2007 | pmid = 17671182 | doi = 10.1158/0008-5472.CAN-07-1302 }}</ref><ref name="pmid21070761">{{cite journal | vauthors = Ghaleb AM, McConnell BB, Kaestner KH, Yang VW | title = Altered intestinal epithelial homeostasis in mice with intestine-specific deletion of the Krüppel-like factor 4 gene | journal = Developmental Biology | volume = 349 | issue = 2 | pages = 310–20 | date = January 2011 | pmid = 21070761 | doi = 10.1016/j.ydbio.2010.11.001 }}</ref> In the intestinal epithelium, KLF4 is an important regulator of [[Wnt signaling pathway]] genes of genes regulating differentiation.<ref name="pmid21070761" />
 
KLF4 is expressed in a variety of tissues and organs such as: the [[cornea]] where it is required for epithelial barrier function<ref>{{cite journal | vauthors = Norman B, Davis J, Piatigorsky J | title = Postnatal gene expression in the normal mouse cornea by SAGE | journal = Investigative Ophthalmology & Visual Science | volume = 45 | issue = 2 | pages = 429–40 | date = February 2004 | pmid = 14744882 }}</ref><ref>{{cite journal | vauthors = Swamynathan S, Kenchegowda D, Piatigorsky J, Swamynathan S | title = Regulation of corneal epithelial barrier function by Kruppel-like transcription factor 4 | journal = Investigative Ophthalmology & Visual Science | volume = 52 | issue = 3 | pages = 1762–9 | date = March 2011 | pmid = 21051695 | doi = 10.1167/iovs.10-6134 }}</ref> and is a regulator of genes required for corneal homeostasis;<ref>{{cite journal | vauthors = Swamynathan SK, Davis J, Piatigorsky J | title = Identification of candidate Klf4 target genes reveals the molecular basis of the diverse regulatory roles of Klf4 in the mouse cornea | journal = Investigative Ophthalmology & Visual Science | volume = 49 | issue = 8 | pages = 3360–70 | date = August 2008 | pmid = 18469187 | doi = 10.1167/iovs.08-1811 }}</ref> the [[skin]] where it is required for the development of skin permeability barrier function;<ref>{{cite journal | vauthors = Segre JA, Bauer C, Fuchs E | title = Klf4 is a transcription factor required for establishing the barrier function of the skin | journal = Nature Genetics | volume = 22 | issue = 4 | pages = 356–60 | date = August 1999 | pmid = 10431239 | doi = 10.1038/11926 }}</ref><ref>{{cite journal | vauthors = Jaubert J, Cheng J, Segre JA | title = Ectopic expression of kruppel like factor 4 (Klf4) accelerates formation of the epidermal permeability barrier | journal = Development | volume = 130 | issue = 12 | pages = 2767–77 | date = June 2003 | pmid = 12736219 }}</ref><ref>{{cite journal | vauthors = Li J, Zheng H, Yu F, Yu T, Liu C, Huang S, Wang TC, Ai W | title = Deficiency of the Kruppel-like factor KLF4 correlates with increased cell proliferation and enhanced skin tumorigenesis | journal = Carcinogenesis | volume = 33 | issue = 6 | pages = 1239–46 | date = June 2012 | pmid = 22491752 | doi = 10.1093/carcin/bgs143 }}</ref> the [[bone]] and teeth tissues where it regulates normal skeletal development;<ref>{{cite journal | vauthors = Michikami I, Fukushi T, Tanaka M, Egusa H, Maeda Y, Ooshima T, Wakisaka S, Abe M | title = Krüppel-like factor 4 regulates membranous and endochondral ossification | journal = Experimental Cell Research | volume = 318 | issue = 4 | pages = 311–25 | date = February 2012 | pmid = 22206865 | doi = 10.1016/j.yexcr.2011.12.013 }}</ref><ref>{{cite journal | vauthors = Fujikawa J, Tanaka M, Itoh S, Fukushi T, Kurisu K, Takeuchi Y, Morisaki I, Wakisaka S, Abe M | title = Kruppel-like factor 4 expression in osteoblasts represses osteoblast-dependent osteoclast maturation | journal = Cell and Tissue Research | volume = 358 | issue = 1 | pages = 177–87 | date = October 2014 | pmid = 24927920 | doi = 10.1007/s00441-014-1931-8 }}</ref><ref>{{cite journal | vauthors = Kim JH, Kim K, Youn BU, Lee J, Kim I, Shin HI, Akiyama H, Choi Y, Kim N | title = Kruppel-like factor 4 attenuates osteoblast formation, function, and cross talk with osteoclasts | journal = The Journal of Cell Biology | volume = 204 | issue = 6 | pages = 1063–74 | date = March 2014 | pmid = 24616223 | doi = 10.1083/jcb.201308102 }}</ref><ref>{{cite journal | vauthors = Chen Z, Couble ML, Mouterfi N, Magloire H, Chen Z, Bleicher F | title = Spatial and temporal expression of KLF4 and KLF5 during murine tooth development | journal = Archives of Oral Biology | volume = 54 | issue = 5 | pages = 403–11 | date = May 2009 | pmid = 19268913 | doi = 10.1016/j.archoralbio.2009.02.003 }}</ref> epithelial cell of the mouse male and female reproductive tract<ref>{{cite journal | vauthors = Godmann M, Kosan C, Behr R | title = Krüppel-like factor 4 is widely expressed in the mouse male and female reproductive tract and responds as an immediate early gene to activation of the protein kinase A in TM4 Sertoli cells | journal = Reproduction | volume = 139 | issue = 4 | pages = 771–82 | date = April 2010 | pmid = 20051481 | doi = 10.1530/REP-09-0531 }}</ref> where in the males it is important for proper spermatogenesis;<ref>{{cite journal | vauthors = Behr R, Kaestner KH | title = Developmental and cell type-specific expression of the zinc finger transcription factor Krüppel-like factor 4 (Klf4) in postnatal mouse testis | journal = Mechanisms of Development | volume = 115 | issue = 1-2 | pages = 167–9 | date = July 2002 | pmid = 12049784 }}</ref><ref>{{cite journal | vauthors = Sze KL, Lee WM, Lui WY | title = Expression of CLMP, a novel tight junction protein, is mediated via the interaction of GATA with the Kruppel family proteins, KLF4 and Sp1, in mouse TM4 Sertoli cells | journal = Journal of Cellular Physiology | volume = 214 | issue = 2 | pages = 334–44 | date = February 2008 | pmid = 17620326 | doi = 10.1002/jcp.21201 }}</ref><ref>{{cite journal | vauthors = Godmann M, Katz JP, Guillou F, Simoni M, Kaestner KH, Behr R | title = Krüppel-like factor 4 is involved in functional differentiation of testicular Sertoli cells | journal = Developmental Biology | volume = 315 | issue = 2 | pages = 552–66 | date = March 2008 | pmid = 18243172 | doi = 10.1016/j.ydbio.2007.12.018 }}</ref> vascular endothelial cells<ref>{{cite journal | vauthors = Hamik A, Lin Z, Kumar A, Balcells M, Sinha S, Katz J, Feinberg MW, Gerzsten RE, Edelman ER, Jain MK | title = Kruppel-like factor 4 regulates endothelial inflammation | journal = The Journal of Biological Chemistry | volume = 282 | issue = 18 | pages = 13769–79 | date = May 2007 | pmid = 17339326 | doi = 10.1074/jbc.M700078200 }}</ref> where it is critical in preventing vascular leakage in response to inflammatory stimuli;<ref>{{cite journal | vauthors = Cowan CE, Kohler EE, Dugan TA, Mirza MK, Malik AB, Wary KK | title = Kruppel-like factor-4 transcriptionally regulates VE-cadherin expression and endothelial barrier function | journal = Circulation Research | volume = 107 | issue = 8 | pages = 959–66 | date = October 2010 | pmid = 20724706 | doi = 10.1161/CIRCRESAHA.110.219592 }}</ref> white blood cells where it mediates inflammatory responses cellular differentiation<ref>{{cite journal | vauthors = Zhang P, Basu P, Redmond LC, Morris PE, Rupon JW, Ginder GD, Lloyd JA | title = A functional screen for Krüppel-like factors that regulate the human gamma-globin gene through the CACCC promoter element | journal = Blood Cells, Molecules & Diseases | volume = 35 | issue = 2 | pages = 227–35 | pmid = 16023392 | doi = 10.1016/j.bcmd.2005.04.009 }}</ref><ref>{{cite journal | vauthors = Liu J, Zhang H, Liu Y, Wang K, Feng Y, Liu M, Xiao X | title = KLF4 regulates the expression of interleukin-10 in RAW264.7 macrophages | journal = Biochemical and Biophysical Research Communications | volume = 362 | issue = 3 | pages = 575–81 | date = October 2007 | pmid = 17719562 | doi = 10.1016/j.bbrc.2007.07.157 }}</ref><ref>{{cite journal | vauthors = Feinberg MW, Wara AK, Cao Z, Lebedeva MA, Rosenbauer F, Iwasaki H, Hirai H, Katz JP, Haspel RL, Gray S, Akashi K, Segre J, Kaestner KH, Tenen DG, Jain MK | title = The Kruppel-like factor KLF4 is a critical regulator of monocyte differentiation | journal = The EMBO Journal | volume = 26 | issue = 18 | pages = 4138–48 | date = September 2007 | pmid = 17762869 | doi = 10.1038/sj.emboj.7601824 }}</ref><ref name="pmid17878366">{{cite journal | vauthors = Klaewsongkram J, Yang Y, Golech S, Katz J, Kaestner KH, Weng NP | title = Krüppel-like factor 4 regulates B cell number and activation-induced B cell proliferation | journal = Journal of Immunology | volume = 179 | issue = 7 | pages = 4679–84 | date = October 2007 | pmid = 17878366 }}</ref> and proliferation;<ref name="pmid17878366" /><ref>{{cite journal | vauthors = Yusuf I, Kharas MG, Chen J, Peralta RQ, Maruniak A, Sareen P, Yang VW, Kaestner KH, Fruman DA | title = KLF4 is a FOXO target gene that suppresses B cell proliferation | journal = International Immunology | volume = 20 | issue = 5 | pages = 671–81 | date = May 2008 | pmid = 18375530 | doi = 10.1093/intimm/dxn024 }}</ref> the kidneys where it is involved in the differentiation of embryonic stem cells and induced pluripotent stem (iPS) cells to renal lineage in vitro<ref>{{cite journal | vauthors = Song B, Niclis JC, Alikhan MA, Sakkal S, Sylvain A, Kerr PG, Laslett AL, Bernard CA, Ricardo SD | title = Generation of induced pluripotent stem cells from human kidney mesangial cells | journal = Journal of the American Society of Nephrology | volume = 22 | issue = 7 | pages = 1213–20 | date = July 2011 | pmid = 21566060 | doi = 10.1681/ASN.2010101022 }}</ref> and its dysregulation has been linked to some renal pathologies.<ref>{{cite journal | vauthors = Hayashi K, Sasamura H, Nakamura M, Sakamaki Y, Azegami T, Oguchi H, Tokuyama H, Wakino S, Hayashi K, Itoh H | title = Renin-angiotensin blockade resets podocyte epigenome through Kruppel-like Factor 4 and attenuates proteinuria | journal = Kidney International | volume = 88 | issue = 4 | pages = 745–53 | date = October 2015 | pmid = 26108068 | doi = 10.1038/ki.2015.178 }}</ref><ref>{{cite journal | vauthors = Mreich E, Chen XM, Zaky A, Pollock CA, Saad S | title = The role of Krüppel-like factor 4 in transforming growth factor-β-induced inflammatory and fibrotic responses in human proximal tubule cells | journal = Clinical and Experimental Pharmacology & Physiology | volume = 42 | issue = 6 | pages = 680–6 | date = June 2015 | pmid = 25882815 | doi = 10.1111/1440-1681.12405 }}</ref><ref>{{cite journal | vauthors = Chen WC, Lin HH, Tang MJ | title = Matrix-Stiffness-Regulated Inverse Expression of Krüppel-Like Factor 5 and Krüppel-Like Factor 4 in the Pathogenesis of Renal Fibrosis | journal = The American Journal of Pathology | volume = 185 | issue = 9 | pages = 2468–81 | date = September 2015 | pmid = 26212907 | doi = 10.1016/j.ajpath.2015.05.019 }}</ref>
 
==Roles in diseases==
Several lines of evidence have shown that KLF4 role in disease is context dependent where under certain conditions it may play one role and under different conditions it may assume a complete opposite role.
   
KLF4 is an anti-tumorigenic factor and its expression is often lost in various human cancer types, such as [[Colorectal cancer]],<ref>{{cite journal | vauthors = Zhao W, Hisamuddin IM, Nandan MO, Babbin BA, Lamb NE, Yang VW | title = Identification of Krüppel-like factor 4 as a potential tumor suppressor gene in colorectal cancer | journal = Oncogene | volume = 23 | issue = 2 | pages = 395–402 | date = January 2004 | pmid = 14724568 | doi = 10.1038/sj.onc.1207067 }}</ref> [[gastric cancer]],<ref>{{cite journal | vauthors = Wei D, Gong W, Kanai M, Schlunk C, Wang L, Yao JC, Wu TT, Huang S, Xie K | title = Drastic down-regulation of Krüppel-like factor 4 expression is critical in human gastric cancer development and progression | journal = Cancer Research | volume = 65 | issue = 7 | pages = 2746–54 | date = April 2005 | pmid = 15805274 | doi = 10.1158/0008-5472.CAN-04-3619 }}</ref> esophageal squamous cell carcinoma,<ref>{{cite journal | vauthors = Yang Y, Goldstein BG, Chao HH, Katz JP | title = KLF4 and KLF5 regulate proliferation, apoptosis and invasion in esophageal cancer cells | journal = Cancer Biology & Therapy | volume = 4 | issue = 11 | pages = 1216–21 | date = November 2005 | pmid = 16357509 }}</ref> intestinal cancer,<ref>{{cite journal | vauthors = Ton-That H, Kaestner KH, Shields JM, Mahatanankoon CS, Yang VW | title = Expression of the gut-enriched Krüppel-like factor gene during development and intestinal tumorigenesis | journal = FEBS Letters | volume = 419 | issue = 2-3 | pages = 239–43 | date = December 1997 | pmid = 9428642 }}</ref> [[prostate cancer]],<ref>{{cite journal | vauthors = Schulz WA, Hatina J | title = Epigenetics of prostate cancer: beyond DNA methylation | journal = Journal of Cellular and Molecular Medicine | volume = 10 | issue = 1 | pages = 100–25 | date = January 2006 | pmid = 16563224 }}</ref> [[bladder cancer]]<ref>{{cite journal | vauthors = Ohnishi S, Ohnami S, Laub F, Aoki K, Suzuki K, Kanai Y, Haga K, Asaka M, Ramirez F, Yoshida T | title = Downregulation and growth inhibitory effect of epithelial-type Krüppel-like transcription factor KLF4, but not KLF5, in bladder cancer | journal = Biochemical and Biophysical Research Communications | volume = 308 | issue = 2 | pages = 251–6 | date = August 2003 | pmid = 12901861 }}</ref> and [[lung cancer]].<ref>{{cite journal | vauthors = Hu W, Hofstetter WL, Li H, Zhou Y, He Y, Pataer A, Wang L, Xie K, Swisher SG, Fang B | title = Putative tumor-suppressive function of Kruppel-like factor 4 in primary lung carcinoma | journal = Clinical Cancer Research | volume = 15 | issue = 18 | pages = 5688–95 | date = September 2009 | pmid = 19737957 | doi = 10.1158/1078-0432.CCR-09-0310 }}</ref>
 
However, in some cancer types KLF4 may act as a tumor promoter where increased KLF4 expression has been reported, such as in oral squamous cell carcinoma<ref>{{cite journal | vauthors = Foster KW, Ren S, Louro ID, Lobo-Ruppert SM, McKie-Bell P, Grizzle W, Hayes MR, Broker TR, Chow LT, Ruppert JM | title = Oncogene expression cloning by retroviral transduction of adenovirus E1A-immortalized rat kidney RK3E cells: transformation of a host with epithelial features by c-MYC and the zinc finger protein GKLF | journal = Cell Growth & Differentiation | volume = 10 | issue = 6 | pages = 423–34 | date = June 1999 | pmid = 10392904 }}</ref> and in primary breast ductal carcinoma.<ref>{{cite journal | vauthors = Foster KW, Frost AR, McKie-Bell P, Lin CY, Engler JA, Grizzle WE, Ruppert JM | title = Increase of GKLF messenger RNA and protein expression during progression of breast cancer | journal = Cancer Research | volume = 60 | issue = 22 | pages = 6488–95 | date = November 2000 | pmid = 11103818 }}</ref> Also, overexpression of KLF4 in skin resulted in [[hyperplasia]] and [[dysplasia]],<ref>{{cite journal | vauthors = Foster KW, Liu Z, Nail CD, Li X, Fitzgerald TJ, Bailey SK, Frost AR, Louro ID, Townes TM, Paterson AJ, Kudlow JE, Lobo-Ruppert SM, Ruppert JM | title = Induction of KLF4 in basal keratinocytes blocks the proliferation-differentiation switch and initiates squamous epithelial dysplasia | journal = Oncogene | volume = 24 | issue = 9 | pages = 1491–500 | date = February 2005 | pmid = 15674344 | doi = 10.1038/sj.onc.1208307 }}</ref> which lead to the development of squamous cell carcinoma.<ref>{{cite journal | vauthors = Huang CC, Liu Z, Li X, Bailey SK, Nail CD, Foster KW, Frost AR, Ruppert JM, Lobo-Ruppert SM | title = KLF4 and PCNA identify stages of tumor initiation in a conditional model of cutaneous squamous epithelial neoplasia | journal = Cancer Biology & Therapy | volume = 4 | issue = 12 | pages = 1401–8 | date = December 2005 | pmid = 16357510 }}</ref> Similar finding in esophageal epithelium was observed, where overexpression of KLF4 resulted in increased inflammation that eventually lead to the development of esophageal squamous cell cancer in mice.<ref>{{cite journal | vauthors = Tetreault MP, Wang ML, Yang Y, Travis J, Yu QC, Klein-Szanto AJ, Katz JP | title = Klf4 overexpression activates epithelial cytokines and inflammation-mediated esophageal squamous cell cancer in mice | journal = Gastroenterology | volume = 139 | issue = 6 | pages = 2124–2134.e9 | date = December 2010 | pmid = 20816834 | doi = 10.1053/j.gastro.2010.08.048 }}</ref>
 
The role of KLF4 in [[Epithelial–mesenchymal transition]] (EMT) is also controversial. It was shown to stimulate EMT in some systems by promoting/maintaining stemness of cancer cells, as is the case in [[pancreatic cancer]],<ref>{{cite journal | vauthors = Pinho AV, Rooman I, Real FX | title = p53-dependent regulation of growth, epithelial-mesenchymal transition and stemness in normal pancreatic epithelial cells | journal = Cell Cycle | volume = 10 | issue = 8 | pages = 1312–21 | date = April 2011 | pmid = 21490434 | doi = 10.4161/cc.10.8.15363 }}</ref><ref>{{cite journal | vauthors = Sureban SM, May R, Qu D, Weygant N, Chandrakesan P, Ali N, Lightfoot SA, Pantazis P, Rao CV, Postier RG, Houchen CW | title = DCLK1 regulates pluripotency and angiogenic factors via microRNA-dependent mechanisms in pancreatic cancer | journal = PloS One | volume = 8 | issue = 9 | pages = e73940 | date = 9 September 2013 | pmid = 24040120 | doi = 10.1371/journal.pone.0073940 }}</ref><ref>{{cite journal | vauthors = Wellner U, Schubert J, Burk UC, Schmalhofer O, Zhu F, Sonntag A, Waldvogel B, Vannier C, Darling D, zur Hausen A, Brunton VG, Morton J, Sansom O, Schüler J, Stemmler MP, Herzberger C, Hopt U, Keck T, Brabletz S, Brabletz T | title = The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs | journal = Nature Cell Biology | volume = 11 | issue = 12 | pages = 1487–95 | date = December 2009 | pmid = 19935649 | doi = 10.1038/ncb1998 }}</ref> head and neck cancer,<ref>{{cite journal | vauthors = Chen Z, Wang Y, Liu W, Zhao G, Lee S, Balogh A, Zou Y, Guo Y, Zhang Z, Gu W, Li C, Tigyi G, Yue J | title = Doxycycline inducible Krüppel-like factor 4 lentiviral vector mediates mesenchymal to epithelial transition in ovarian cancer cells | journal = PloS One | volume = 9 | issue = 8 | pages = e105331 | date = 19 August 2014 | pmid = 25137052 | doi = 10.1371/journal.pone.0105331 }}</ref> [[endometrial cancer]],<ref>{{cite journal | vauthors = Dong P, Kaneuchi M, Watari H, Hamada J, Sudo S, Ju J, Sakuragi N | title = MicroRNA-194 inhibits epithelial to mesenchymal transition of endometrial cancer cells by targeting oncogene BMI-1 | journal = Molecular Cancer | volume = 10 | pages = 99 | date = August 2011 | pmid = 21851624 | doi = 10.1186/1476-4598-10-99 }}</ref> [[nasopharyngeal cancer]],<ref>{{cite journal | vauthors = Wu A, Luo W, Zhang Q, Yang Z, Zhang G, Li S, Yao K | title = Aldehyde dehydrogenase 1, a functional marker for identifying cancer stem cells in human nasopharyngeal carcinoma | journal = Cancer Letters | volume = 330 | issue = 2 | pages = 181–9 | date = April 2013 | pmid = 23220285 | doi = 10.1016/j.canlet.2012.11.046 }}</ref> prostate cancer<ref>{{cite journal | vauthors = Ren D, Wang M, Guo W, Zhao X, Tu X, Huang S, Zou X, Peng X | title = Wild-type p53 suppresses the epithelial-mesenchymal transition and stemness in PC-3 prostate cancer cells by modulating miR‑145 | journal = International Journal of Oncology | volume = 42 | issue = 4 | pages = 1473–81 | date = April 2013 | pmid = 23404342 | doi = 10.3892/ijo.2013.1825 }}</ref> and non-small lung cancer.<ref>{{cite journal | vauthors = Kumar M, Allison DF, Baranova NN, Wamsley JJ, Katz AJ, Bekiranov S, Jones DR, Mayo MW | title = NF-κB regulates mesenchymal transition for the induction of non-small cell lung cancer initiating cells | journal = PloS One | volume = 8 | issue = 7 | pages = e68597 | date = 2013 | pmid = 23935876 | doi = 10.1371/journal.pone.0068597 }}</ref> Under conditions of TGFβ-induced EMT KLF4 was shown to suppress EMT in the same systems where it was shown to promote EMT, such as prostate cancer<ref>{{cite journal | vauthors = Liu YN, Abou-Kheir W, Yin JJ, Fang L, Hynes P, Casey O, Hu D, Wan Y, Seng V, Sheppard-Tillman H, Martin P, Kelly K | title = Critical and reciprocal regulation of KLF4 and SLUG in transforming growth factor β-initiated prostate cancer epithelial-mesenchymal transition | journal = Molecular and Cellular Biology | volume = 32 | issue = 5 | pages = 941–53 | date = March 2012 | pmid = 22203039 | doi = 10.1128/MCB.06306-11 }}</ref> and pancreatic cancer.<ref>{{cite journal | vauthors = Ouyang H, Gore J, Deitz S, Korc M | title = microRNA-10b enhances pancreatic cancer cell invasion by suppressing TIP30 expression and promoting EGF and TGF-β actions | journal = Oncogene | volume = 33 | issue = 38 | pages = 4664–74 | date = September 2014 | pmid = 24096486 | doi = 10.1038/onc.2013.405 }}</ref> Additionally, KLF4 was shown to suppress EMT in epidermal cancer,<ref>{{cite journal | vauthors = Mistry DS, Chen Y, Wang Y, Zhang K, Sen GL | title = SNAI2 controls the undifferentiated state of human epidermal progenitor cells | journal = Stem Cells | volume = 32 | issue = 12 | pages = 3209–18 | date = December 2014 | pmid = 25100569 | doi = 10.1002/stem.1809 }}</ref> breast cancer,<ref>{{cite journal | vauthors = Wang B, Zhao MZ, Cui NP, Lin DD, Zhang AY, Qin Y, Liu CY, Yan WT, Shi JH, Chen BP | title = Krüppel-like factor 4 induces apoptosis and inhibits tumorigenic progression in SK-BR-3 breast cancer cells | journal = FEBS Open Bio | volume = 5 | pages = 147–54 | date = 2 March 2015 | pmid = 25834779 | doi = 10.1016/j.fob.2015.02.003 }}</ref> lung cancer,<ref>{{cite journal | vauthors = Liu S, Yang H, Chen Y, He B, Chen Q | title = Krüppel-Like Factor 4 Enhances Sensitivity of Cisplatin to Lung Cancer Cells and Inhibits Regulating Epithelial-to-Mesenchymal Transition | journal = Oncology Research | volume = 24 | issue = 2 | pages = 81–7 | date = 2016 | pmid = 27296948 | doi = 10.3727/096504016X14597766487717 }}</ref> cisplatin-resistant nasopharyngeal carcinoma cells,<ref>{{cite journal | vauthors = Zhang P, Hong H, Sun X, Jiang H, Ma S, Zhao S, Zhang M, Wang Z, Jiang C, Liu H | title = MicroRNA-10b regulates epithelial-mesenchymal transition by modulating KLF4/Notch1/E-cadherin in cisplatin-resistant nasopharyngeal carcinoma cells | journal = American Journal of Cancer Research | volume = 6 | issue = 2 | pages = 141–56 | date = 15 January 2016 | pmid = 27186392 }}</ref> and in hepatocellular carcinoma cells.<ref>{{cite journal | vauthors = Li Q, Song W, Wang W, Yao S, Tian C, Cai X, Wang L | title = Suppression of epithelial-mesenchymal transition in hepatocellular carcinoma cells by Krüppel-like factor 4 | journal = Oncotarget | volume = 7 | issue = 20 | pages = 29749–60 | date = May 2016 | pmid = 27102441 | doi = 10.18632/oncotarget.8831 }}</ref>
 
KLF4 plays an important role in several vascular diseases where it was shown to regulate vascular inflammation by controlling macrophage polarization<ref>{{cite journal | vauthors = Liao X, Sharma N, Kapadia F, Zhou G, Lu Y, Hong H, Paruchuri K, Mahabeleshwar GH, Dalmas E, Venteclef N, Flask CA, Kim J, Doreian BW, Lu KQ, Kaestner KH, Hamik A, Clément K, Jain MK | title = Krüppel-like factor 4 regulates macrophage polarization | journal = The Journal of Clinical Investigation | volume = 121 | issue = 7 | pages = 2736–49 | date = July 2011 | pmid = 21670502 | doi = 10.1172/JCI45444 }}</ref> and plaque formation in [[atherosclerosis]].<ref>{{cite journal | vauthors = Sharma N, Lu Y, Zhou G, Liao X, Kapil P, Anand P, Mahabeleshwar GH, Stamler JS, Jain MK | title = Myeloid Krüppel-like factor 4 deficiency augments atherogenesis in ApoE-/- mice--brief report | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 32 | issue = 12 | pages = 2836–8 | date = December 2012 | pmid = 23065827 | doi = 10.1161/ATVBAHA.112.300471 }}</ref><ref name="pmid26546821">{{cite journal | vauthors = Stavri S, Simionescu M, Kardassis D, Gafencu AV | title = Krüppel-like factor 4 synergizes with CREB to increase the activity of apolipoprotein E gene promoter in macrophages | journal = Biochemical and Biophysical Research Communications | volume = 468 | issue = 1-2 | pages = 66–72 | date = December 2015 | pmid = 26546821 | doi = 10.1016/j.bbrc.2015.10.163 }}</ref><ref>{{cite journal | vauthors = Hale AT, Longenecker CT, Jiang Y, Debanne SM, Labatto DE, Storer N, Hamik A, McComsey GA | title = HIV vasculopathy: role of mononuclear cell-associated Krüppel-like factors 2 and 4 | journal = Aids | volume = 29 | issue = 13 | pages = 1643–50 | date = August 2015 | pmid = 26372274 | doi = 10.1097/QAD.0000000000000756 }}</ref> It up-regulates [[Apolipoprotein E]], which is an anti-atherosclerotic factor.<ref name="pmid26546821" /> It is also involved in the regulation of [[angiogenesis]]. It may suppress angiogenesis by regulating [[NOTCH1]] activity,<ref>{{cite journal | vauthors = Hale AT, Tian H, Anih E, Recio FO, Shatat MA, Johnson T, Liao X, Ramirez-Bergeron DL, Proweller A, Ishikawa M, Hamik A | title = Endothelial Kruppel-like factor 4 regulates angiogenesis and the Notch signaling pathway | journal = The Journal of Biological Chemistry | volume = 289 | issue = 17 | pages = 12016–28 | date = April 2014 | pmid = 24599951 | doi = 10.1074/jbc.M113.530956 }}</ref> while in the central nervous system its overexpression leads to vascular dysplasia.<ref>{{cite journal | vauthors = Cuttano R, Rudini N, Bravi L, Corada M, Giampietro C, Papa E, Morini MF, Maddaluno L, Baeyens N, Adams RH, Jain MK, Owens GK, Schwartz M, Lampugnani MG, Dejana E | title = KLF4 is a key determinant in the development and progression of cerebral cavernous malformations | journal = EMBO Molecular Medicine | volume = 8 | issue = 1 | pages = 6–24 | date = November 2015 | pmid = 26612856 | doi = 10.15252/emmm.201505433 }}</ref>
 
KLF4 may promote inflammation by mediating NF-κB-dependent inflammatory pathway such as in macrophages,<ref>{{cite journal | vauthors = Feinberg MW, Cao Z, Wara AK, Lebedeva MA, Senbanerjee S, Jain MK | title = Kruppel-like factor 4 is a mediator of proinflammatory signaling in macrophages | journal = The Journal of Biological Chemistry | volume = 280 | issue = 46 | pages = 38247–58 | date = November 2005 | pmid = 16169848 | doi = 10.1074/jbc.M509378200 }}</ref> esophageal epithelium<ref>{{cite journal | vauthors = Tetreault MP, Wang ML, Yang Y, Travis J, Yu QC, Klein-Szanto AJ, Katz JP | title = Klf4 overexpression activates epithelial cytokines and inflammation-mediated esophageal squamous cell cancer in mice | journal = Gastroenterology | volume = 139 | issue = 6 | pages = 2124–2134.e9 | date = December 2010 | pmid = 20816834 | doi = 10.1053/j.gastro.2010.08.048 }}</ref> and in chemically-induced acute colitis in mice.<ref>{{cite journal | vauthors = Ghaleb AM, Laroui H, Merlin D, Yang VW | title = Genetic deletion of Klf4 in the mouse intestinal epithelium ameliorates dextran sodium sulfate-induced colitis by modulating the NF-κB pathway inflammatory response | journal = Inflammatory Bowel Diseases | volume = 20 | issue = 5 | pages = 811–20 | date = May 2014 | pmid = 24681655 | doi = 10.1097/MIB.0000000000000022 }}</ref> However, KLF4 may also suppress the activation of inflammatory signaling such as in endothelial cells in response to pro-inflammatory stimuli.<ref>{{cite journal | vauthors = Hamik A, Lin Z, Kumar A, Balcells M, Sinha S, Katz J, Feinberg MW, Gerzsten RE, Edelman ER, Jain MK | title = Kruppel-like factor 4 regulates endothelial inflammation | journal = The Journal of Biological Chemistry | volume = 282 | issue = 18 | pages = 13769–79 | date = May 2007 | pmid = 17339326 | doi = 10.1074/jbc.M700078200 }}</ref>


<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
KLF4 is essential for the cellular response to DNA damage. It is required for preventing cell cycle entry into mitosis following γ-irradiation-induced DNA damage,<ref>{{cite journal | vauthors = Yoon HS, Yang VW | title = Requirement of Krüppel-like factor 4 in preventing entry into mitosis following DNA damage | journal = The Journal of Biological Chemistry | volume = 279 | issue = 6 | pages = 5035–41 | date = February 2004 | pmid = 14627709 | doi = 10.1074/jbc.M307631200 }}</ref><ref>{{cite journal | vauthors = Yoon HS, Chen X, Yang VW | title = Kruppel-like factor 4 mediates p53-dependent G1/S cell cycle arrest in response to DNA damage | journal = The Journal of Biological Chemistry | volume = 278 | issue = 4 | pages = 2101–5 | date = January 2003 | pmid = 12427745 | doi = 10.1074/jbc.M211027200 }}</ref> in promoting DNA repair mechanisms (20) and in preventing the irradiated cell from undergoing programmed cell death (apoptosis) (23,25,26).<ref>{{cite journal | vauthors = Rowland BD, Bernards R, Peeper DS | title = The KLF4 tumour suppressor is a transcriptional repressor of p53 that acts as a context-dependent oncogene | journal = Nature Cell Biology | volume = 7 | issue = 11 | pages = 1074–82 | date = November 2005 | pmid = 16244670 | doi = 10.1038/ncb1314 }}</ref><ref>{{cite journal | vauthors = McConnell BB, Ghaleb AM, Nandan MO, Yang VW | title = The diverse functions of Krüppel-like factors 4 and 5 in epithelial biology and pathobiology | journal = BioEssays | volume = 29 | issue = 6 | pages = 549–57 | date = June 2007 | pmid = 17508399 | doi = 10.1002/bies.20581 }}</ref><ref name="pmid25414097">{{cite journal | vauthors = Talmasov D, Xinjun Z, Yu B, Nandan MO, Bialkowska AB, Elkarim E, Kuruvilla J, Yang VW, Ghaleb AM | title = Krüppel-like factor 4 is a radioprotective factor for the intestine following γ-radiation-induced gut injury in mice | journal = American Journal of Physiology. Gastrointestinal and Liver Physiology | volume = 308 | issue = 2 | pages = G121-38 | date = January 2015 | pmid = 25414097 | doi = 10.1152/ajpgi.00080.2014 }}</ref> In one study, the in vivo importance of KLF4 in response to γ-irradiation-induced DNA damage was revealed where deletion of KLF4 specifically from the intestinal epithelium in mice lead to inability of the intestinal epithelium to regenerate and resulting in increased mortality of these mice.<ref name="pmid25414097" />
{{GNF_Protein_box
| image =
| image_source =
| PDB =
| Name = Kruppel-like factor 4 (gut)
| HGNCid = 6348
| Symbol = KLF4
| AltSymbols =; EZF; GKLF
| OMIM = 602253
| ECnumber =
| Homologene = 3123
| MGIid = 1342287
| GeneAtlas_image1 = PBB_GE_KLF4_221841_s_at_tn.png
| GeneAtlas_image2 = PBB_GE_KLF4_220266_s_at_tn.png
| Function = {{GNF_GO|id=GO:0003676 |text = nucleic acid binding}} {{GNF_GO|id=GO:0003700 |text = transcription factor activity}} {{GNF_GO|id=GO:0008270 |text = zinc ion binding}} {{GNF_GO|id=GO:0016563 |text = transcription activator activity}} {{GNF_GO|id=GO:0016564 |text = transcription repressor activity}} {{GNF_GO|id=GO:0046872 |text = metal ion binding}}  
| Component = {{GNF_GO|id=GO:0005622 |text = intracellular}} {{GNF_GO|id=GO:0005634 |text = nucleus}}
| Process = {{GNF_GO|id=GO:0006350 |text = transcription}} {{GNF_GO|id=GO:0007500 |text = mesodermal cell fate determination}} {{GNF_GO|id=GO:0008285 |text = negative regulation of cell proliferation}} {{GNF_GO|id=GO:0045892 |text = negative regulation of transcription, DNA-dependent}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 9314
    | Hs_Ensembl = ENSG00000136826
    | Hs_RefseqProtein = NP_004226
    | Hs_RefseqmRNA = NM_004235
    | Hs_GenLoc_db =
    | Hs_GenLoc_chr = 9
    | Hs_GenLoc_start = 109286954
    | Hs_GenLoc_end = 109291748
    | Hs_Uniprot = O43474
    | Mm_EntrezGene = 16600
    | Mm_Ensembl = ENSMUSG00000003032
    | Mm_RefseqmRNA = NM_010637
    | Mm_RefseqProtein = NP_034767
    | Mm_GenLoc_db =
    | Mm_GenLoc_chr = 4
    | Mm_GenLoc_start = 55548365
    | Mm_GenLoc_end = 55553566
    | Mm_Uniprot = Q3U2D6
  }}
}}
'''Kruppel-like factor 4 (gut)''', also known as '''KLF4''', is a human [[gene]].<ref>{{cite web | title = Entrez Gene: KLF4 Kruppel-like factor 4 (gut)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9314| accessdate = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot. See Template:PBB_Controls to Stop updates. -->
==Importance in Stem cells==
{{PBB_Summary
Takahashi and Yamanaka were the first identify KLF4 as one of four factors that are required to induce mouse embryonic and adult fibroblasts into pluripotent stem cells (iPS).<ref>{{cite journal | vauthors = Takahashi K, Yamanaka S | title = Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors | journal = Cell | volume = 126 | issue = 4 | pages = 663–76 | date = August 2006 | pmid = 16904174 | doi = 10.1016/j.cell.2006.07.024 }}</ref> This was also found to be true for adult human [[fibroblasts]].<ref>{{cite journal | vauthors = Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S | title = Induction of pluripotent stem cells from adult human fibroblasts by defined factors | journal = Cell | volume = 131 | issue = 5 | pages = 861–72 | date = November 2007 | pmid = 18035408 | doi = 10.1016/j.cell.2007.11.019 }}</ref> Since 2006 up to today, the work on clinically relevant research in stem cells and stem cell induction, has increased dramatically (more than 10,000 research articles, as compared to about 60 between years 1900 to 2005). In vivo functional studies on the role of KLF4 in stem cells are rare. Recently a group investigated the role of KLF4 in a particular population of intestinal stem cells, the Bmi1+ stem cells.<ref>{{cite journal | vauthors = Kuruvilla JG, Kim CK, Ghaleb AM, Bialkowska AB, Kuo CJ, Yang VW | title = Krüppel-like Factor 4 Modulates Development of BMI1(+) Intestinal Stem Cell-Derived Lineage Following γ-Radiation-Induced Gut Injury in Mice | journal = Stem Cell Reports | volume = 6 | issue = 6 | pages = 815–24 | date = June 2016 | pmid = 27237377 | doi = 10.1016/j.stemcr.2016.04.014 }}</ref> This population of intestinal stem cells: are normally slow dividing, are known to be resistant to radiation injury, and are the ones responsible for intestinal epithelium regeneration following radiation injury.<ref>{{cite journal | vauthors = Yan KS, Chia LA, Li X, Ootani A, Su J, Lee JY, Su N, Luo Y, Heilshorn SC, Amieva MR, Sangiorgi E, Capecchi MR, Kuo CJ | title = The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 109 | issue = 2 | pages = 466–71 | date = January 2012 | pmid = 22190486 | doi = 10.1073/pnas.1118857109 }}</ref> The study showed that in the intestine, following -irradiation-induced DNA damage, KLF4 may regulate epithelial regeneration by modulating the fate of Bmi1+ stem cells themselves, and consequently the development of BMI1+ intestinal stem cell-derived lineage.<ref>{{cite journal | vauthors = Kuruvilla JG, Kim CK, Ghaleb AM, Bialkowska AB, Kuo CJ, Yang VW | title = Krüppel-like Factor 4 Modulates Development of BMI1(+) Intestinal Stem Cell-Derived Lineage Following γ-Radiation-Induced Gut Injury in Mice | journal = Stem Cell Reports | volume = 6 | issue = 6 | pages = 815–24 | date = June 2016 | pmid = 27237377 | doi = 10.1016/j.stemcr.2016.04.014 }}</ref>
| section_title =  
| summary_text =  
}}


==See also==
== See also ==
* [[Kruppel-like factors]]
* [[Kruppel-like factors]]


==References==
==Notes==
{{reflist|2}}
{{Academic-written review
| wikidate = 2017
| journal = [[Gene (journal)|Gene]]
| title  = {{#property:P1476|from=Q39151066}}
| authors = {{#property:P2093|from=Q39151066}}
| date    = {{#property:P577|from=Q39151066}}
| volume  = {{#property:P478|from=Q39151066}}
| issue  = {{#property:P433|from=Q39151066}}
| pages  = {{#property:P304|from=Q39151066}}
| doi    = {{#property:P356|from=Q39151066}}
| pmid    = {{#property:P698|from=Q39151066}}
| pmc    = {{#property:P932|from=Q39151066}}
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==Further reading==
== References ==
{{refbegin | 2}}
{{reflist|33em}}
{{PBB_Further_reading
 
| citations =
== Further reading ==
*{{cite journal | author=Rowland BD, Peeper DS |title=KLF4, p21 and context-dependent opposing forces in cancer. |journal=Nat. Rev. Cancer |volume=6 |issue= 1 |pages= 11-23 |year= 2006 |pmid= 16372018 |doi= 10.1038/nrc1780 }}
{{refbegin|33em}}
*{{cite journal | author=Shields JM, Christy RJ, Yang VW |title=Identification and characterization of a gene encoding a gut-enriched Krüppel-like factor expressed during growth arrest. |journal=J. Biol. Chem. |volume=271 |issue= 33 |pages= 20009-17 |year= 1996 |pmid= 8702718 |doi= }}
* {{cite journal | vauthors = Rowland BD, Peeper DS | title = KLF4, p21 and context-dependent opposing forces in cancer | journal = Nature Reviews. Cancer | volume = 6 | issue = 1 | pages = 11–23 | date = January 2006 | pmid = 16372018 | doi = 10.1038/nrc1780 }}
*{{cite journal | author=Garrett-Sinha LA, Eberspaecher H, Seldin MF, de Crombrugghe B |title=A gene for a novel zinc-finger protein expressed in differentiated epithelial cells and transiently in certain mesenchymal cells. |journal=J. Biol. Chem. |volume=271 |issue= 49 |pages= 31384-90 |year= 1997 |pmid= 8940147 |doi= }}
* {{cite journal | vauthors = Shields JM, Christy RJ, Yang VW | title = Identification and characterization of a gene encoding a gut-enriched Krüppel-like factor expressed during growth arrest | journal = The Journal of Biological Chemistry | volume = 271 | issue = 33 | pages = 20009–17 | date = August 1996 | pmid = 8702718 | pmc = 2330254 | doi = 10.1074/jbc.271.33.20009 }}
*{{cite journal | author=Yet SF, McA'Nulty MM, Folta SC, ''et al.'' |title=Human EZF, a Krüppel-like zinc finger protein, is expressed in vascular endothelial cells and contains transcriptional activation and repression domains. |journal=J. Biol. Chem. |volume=273 |issue= 2 |pages= 1026-31 |year= 1998 |pmid= 9422764 |doi= }}
* {{cite journal | vauthors = Garrett-Sinha LA, Eberspaecher H, Seldin MF, de Crombrugghe B | title = A gene for a novel zinc-finger protein expressed in differentiated epithelial cells and transiently in certain mesenchymal cells | journal = The Journal of Biological Chemistry | volume = 271 | issue = 49 | pages = 31384–90 | date = December 1996 | pmid = 8940147 | doi = 10.1074/jbc.271.49.31384 }}
*{{cite journal | author=Zhang W, Shields JM, Sogawa K, ''et al.'' |title=The gut-enriched Krüppel-like factor suppresses the activity of the CYP1A1 promoter in an Sp1-dependent fashion. |journal=J. Biol. Chem. |volume=273 |issue= 28 |pages= 17917-25 |year= 1998 |pmid= 9651398 |doi= }}
* {{cite journal | vauthors = Yet SF, McA'Nulty MM, Folta SC, Yen HW, Yoshizumi M, Hsieh CM, Layne MD, Chin MT, Wang H, Perrella MA, Jain MK, Lee ME | title = Human EZF, a Krüppel-like zinc finger protein, is expressed in vascular endothelial cells and contains transcriptional activation and repression domains | journal = The Journal of Biological Chemistry | volume = 273 | issue = 2 | pages = 1026–31 | date = January 1998 | pmid = 9422764 | doi = 10.1074/jbc.273.2.1026 }}
*{{cite journal | author=Foster KW, Ren S, Louro ID, ''et al.'' |title=Oncogene expression cloning by retroviral transduction of adenovirus E1A-immortalized rat kidney RK3E cells: transformation of a host with epithelial features by c-MYC and the zinc finger protein GKLF. |journal=Cell Growth Differ. |volume=10 |issue= 6 |pages= 423-34 |year= 1999 |pmid= 10392904 |doi=  }}
* {{cite journal | vauthors = Zhang W, Shields JM, Sogawa K, Fujii-Kuriyama Y, Yang VW | title = The gut-enriched Krüppel-like factor suppresses the activity of the CYP1A1 promoter in an Sp1-dependent fashion | journal = The Journal of Biological Chemistry | volume = 273 | issue = 28 | pages = 17917–25 | date = July 1998 | pmid = 9651398 | pmc = 2275057 | doi = 10.1074/jbc.273.28.17917 }}
*{{cite journal | author=Segre JA, Bauer C, Fuchs E |title=Klf4 is a transcription factor required for establishing the barrier function of the skin. |journal=Nat. Genet. |volume=22 |issue= 4 |pages= 356-60 |year= 1999 |pmid= 10431239 |doi= 10.1038/11926 }}
* {{cite journal | vauthors = Foster KW, Ren S, Louro ID, Lobo-Ruppert SM, McKie-Bell P, Grizzle W, Hayes MR, Broker TR, Chow LT, Ruppert JM | title = Oncogene expression cloning by retroviral transduction of adenovirus E1A-immortalized rat kidney RK3E cells: transformation of a host with epithelial features by c-MYC and the zinc finger protein GKLF | journal = Cell Growth & Differentiation | volume = 10 | issue = 6 | pages = 423–34 | date = June 1999 | pmid = 10392904 | doi =  }}
*{{cite journal | author=Geiman DE, Ton-That H, Johnson JM, Yang VW |title=Transactivation and growth suppression by the gut-enriched Krüppel-like factor (Krüppel-like factor 4) are dependent on acidic amino acid residues and protein-protein interaction. |journal=Nucleic Acids Res. |volume=28 |issue= 5 |pages= 1106-13 |year= 2000 |pmid= 10666450 |doi= }}
* {{cite journal | vauthors = Segre JA, Bauer C, Fuchs E | title = Klf4 is a transcription factor required for establishing the barrier function of the skin | journal = Nature Genetics | volume = 22 | issue = 4 | pages = 356–60 | date = August 1999 | pmid = 10431239 | doi = 10.1038/11926 }}
*{{cite journal | author=Zhang W, Geiman DE, Shields JM, ''et al.'' |title=The gut-enriched Kruppel-like factor (Kruppel-like factor 4) mediates the transactivating effect of p53 on the p21WAF1/Cip1 promoter. |journal=J. Biol. Chem. |volume=275 |issue= 24 |pages= 18391-8 |year= 2000 |pmid= 10749849 |doi= 10.1074/jbc.C000062200 }}
* {{cite journal | vauthors = Geiman DE, Ton-That H, Johnson JM, Yang VW | title = Transactivation and growth suppression by the gut-enriched Krüppel-like factor (Krüppel-like factor 4) are dependent on acidic amino acid residues and protein-protein interaction | journal = Nucleic Acids Research | volume = 28 | issue = 5 | pages = 1106–13 | date = March 2000 | pmid = 10666450 | pmc = 102607 | doi = 10.1093/nar/28.5.1106 }}
*{{cite journal | author=Okano J, Opitz OG, Nakagawa H, ''et al.'' |title=The Krüppel-like transcriptional factors Zf9 and GKLF coactivate the human keratin 4 promoter and physically interact. |journal=FEBS Lett. |volume=473 |issue= 1 |pages= 95-100 |year= 2000 |pmid= 10802067 |doi= }}
* {{cite journal | vauthors = Zhang W, Geiman DE, Shields JM, Dang DT, Mahatan CS, Kaestner KH, Biggs JR, Kraft AS, Yang VW | title = The gut-enriched Kruppel-like factor (Kruppel-like factor 4) mediates the transactivating effect of p53 on the p21WAF1/Cip1 promoter | journal = The Journal of Biological Chemistry | volume = 275 | issue = 24 | pages = 18391–8 | date = June 2000 | pmid = 10749849 | pmc = 2231805 | doi = 10.1074/jbc.C000062200 }}
*{{cite journal | author=Higaki Y, Schullery D, Kawata Y, ''et al.'' |title=Synergistic activation of the rat laminin gamma1 chain promoter by the gut-enriched Kruppel-like factor (GKLF/KLF4) and Sp1. |journal=Nucleic Acids Res. |volume=30 |issue= 11 |pages= 2270-9 |year= 2002 |pmid= 12034813 |doi= }}
* {{cite journal | vauthors = Okano J, Opitz OG, Nakagawa H, Jenkins TD, Friedman SL, Rustgi AK | title = The Krüppel-like transcriptional factors Zf9 and GKLF coactivate the human keratin 4 promoter and physically interact | journal = FEBS Letters | volume = 473 | issue = 1 | pages = 95–100 | date = May 2000 | pmid = 10802067 | doi = 10.1016/S0014-5793(00)01468-X }}
*{{cite journal | author=Chen ZY, Shie JL, Tseng CC |title=Gut-enriched Kruppel-like factor represses ornithine decarboxylase gene expression and functions as checkpoint regulator in colonic cancer cells. |journal=J. Biol. Chem. |volume=277 |issue= 48 |pages= 46831-9 |year= 2003 |pmid= 12297499 |doi= 10.1074/jbc.M204816200 }}
* {{cite journal | vauthors = Higaki Y, Schullery D, Kawata Y, Shnyreva M, Abrass C, Bomsztyk K | title = Synergistic activation of the rat laminin gamma1 chain promoter by the gut-enriched Kruppel-like factor (GKLF/KLF4) and Sp1 | journal = Nucleic Acids Research | volume = 30 | issue = 11 | pages = 2270–9 | date = June 2002 | pmid = 12034813 | pmc = 117209 | doi = 10.1093/nar/30.11.2270 }}
*{{cite journal | author=Yoon HS, Chen X, Yang VW |title=Kruppel-like factor 4 mediates p53-dependent G1/S cell cycle arrest in response to DNA damage. |journal=J. Biol. Chem. |volume=278 |issue= 4 |pages= 2101-5 |year= 2003 |pmid= 12427745 |doi= 10.1074/jbc.M211027200 }}
* {{cite journal | vauthors = Chen ZY, Shie JL, Tseng CC | title = Gut-enriched Kruppel-like factor represses ornithine decarboxylase gene expression and functions as checkpoint regulator in colonic cancer cells | journal = The Journal of Biological Chemistry | volume = 277 | issue = 48 | pages = 46831–9 | date = November 2002 | pmid = 12297499 | doi = 10.1074/jbc.M204816200 }}
*{{cite journal | author=Wang N, Liu ZH, Ding F, ''et al.'' |title=Down-regulation of gut-enriched Kruppel-like factor expression in esophageal cancer. |journal=World J. Gastroenterol. |volume=8 |issue= 6 |pages= 966-70 |year= 2003 |pmid= 12439907 |doi=  }}
* {{cite journal | vauthors = Yoon HS, Chen X, Yang VW | title = Kruppel-like factor 4 mediates p53-dependent G1/S cell cycle arrest in response to DNA damage | journal = The Journal of Biological Chemistry | volume = 278 | issue = 4 | pages = 2101–5 | date = January 2003 | pmid = 12427745 | pmc = 2229830 | doi = 10.1074/jbc.M211027200 }}
*{{cite journal | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
* {{cite journal | vauthors = Wang N, Liu ZH, Ding F, Wang XQ, Zhou CN, Wu M | title = Down-regulation of gut-enriched Kruppel-like factor expression in esophageal cancer | journal = World Journal of Gastroenterology | volume = 8 | issue = 6 | pages = 966–70 | date = December 2002 | pmid = 12439907 | doi =  }}
*{{cite journal | author=Chen X, Whitney EM, Gao SY, Yang VW |title=Transcriptional profiling of Krüppel-like factor 4 reveals a function in cell cycle regulation and epithelial differentiation. |journal=J. Mol. Biol. |volume=326 |issue= 3 |pages= 665-77 |year= 2003 |pmid= 12581631 |doi= }}
* {{cite journal | vauthors = Chen X, Whitney EM, Gao SY, Yang VW | title = Transcriptional profiling of Krüppel-like factor 4 reveals a function in cell cycle regulation and epithelial differentiation | journal = Journal of Molecular Biology | volume = 326 | issue = 3 | pages = 665–77 | date = February 2003 | pmid = 12581631 | pmc = 2693487 | doi = 10.1016/S0022-2836(02)01449-3 }}
*{{cite journal | author=Dang DT, Chen X, Feng J, ''et al.'' |title=Overexpression of Krüppel-like factor 4 in the human colon cancer cell line RKO leads to reduced tumorigenecity. |journal=Oncogene |volume=22 |issue= 22 |pages= 3424-30 |year= 2003 |pmid= 12776194 |doi= 10.1038/sj.onc.1206413 }}
* {{cite journal | vauthors = Dang DT, Chen X, Feng J, Torbenson M, Dang LH, Yang VW | title = Overexpression of Krüppel-like factor 4 in the human colon cancer cell line RKO leads to reduced tumorigenecity | journal = Oncogene | volume = 22 | issue = 22 | pages = 3424–30 | date = May 2003 | pmid = 12776194 | pmc = 2275074 | doi = 10.1038/sj.onc.1206413 }}
*{{cite journal | author=Mao Z, Song S, Zhu Y, ''et al.'' |title=Transcriptional regulation of A33 antigen expression by gut-enriched Krüppel-like factor. |journal=Oncogene |volume=22 |issue= 28 |pages= 4434-43 |year= 2003 |pmid= 12853980 |doi= 10.1038/sj.onc.1206508 }}
* {{cite journal | vauthors = Mao Z, Song S, Zhu Y, Yi X, Zhang H, Shang Y, Tong T | title = Transcriptional regulation of A33 antigen expression by gut-enriched Krüppel-like factor | journal = Oncogene | volume = 22 | issue = 28 | pages = 4434–43 | date = July 2003 | pmid = 12853980 | doi = 10.1038/sj.onc.1206508 }}
*{{cite journal | author=Ohnishi S, Ohnami S, Laub F, ''et al.'' |title=Downregulation and growth inhibitory effect of epithelial-type Krüppel-like transcription factor KLF4, but not KLF5, in bladder cancer. |journal=Biochem. Biophys. Res. Commun. |volume=308 |issue= 2 |pages= 251-6 |year= 2003 |pmid= 12901861 |doi=  }}
* {{cite journal | vauthors = Ohnishi S, Ohnami S, Laub F, Aoki K, Suzuki K, Kanai Y, Haga K, Asaka M, Ramirez F, Yoshida T | title = Downregulation and growth inhibitory effect of epithelial-type Krüppel-like transcription factor KLF4, but not KLF5, in bladder cancer | journal = Biochemical and Biophysical Research Communications | volume = 308 | issue = 2 | pages = 251–6 | date = August 2003 | pmid = 12901861 | doi = 10.1016/S0006-291X(03)01356-1 }}
*{{cite journal  | author=Hinnebusch BF, Siddique A, Henderson JW, ''et al.'' |title=Enterocyte differentiation marker intestinal alkaline phosphatase is a target gene of the gut-enriched Kruppel-like factor. |journal=Am. J. Physiol. Gastrointest. Liver Physiol. |volume=286 |issue= 1 |pages= G23-30 |year= 2004 |pmid= 12919939 |doi= 10.1152/ajpgi.00203.2003 }}
* {{cite journal | vauthors = Hinnebusch BF, Siddique A, Henderson JW, Malo MS, Zhang W, Athaide CP, Abedrapo MA, Chen X, Yang VW, Hodin RA | title = Enterocyte differentiation marker intestinal alkaline phosphatase is a target gene of the gut-enriched Kruppel-like factor | journal = American Journal of Physiology. Gastrointestinal and Liver Physiology | volume = 286 | issue = 1 | pages = G23-30 | date = January 2004 | pmid = 12919939 | doi = 10.1152/ajpgi.00203.2003 }}
}}
{{refend}}
{{refend}}


== External links ==
== External links ==
* {{MeshName|KLF4+protein,+human}}
* {{MeshName|KLF4+protein,+human}}
* [http://www.nextbio.com/b/home/home.nb?q=KLF4&id=34891&type=feature&name=KLF4&synonym= KLF4 microarray expression results and literature]
{{Transcription factors|g2}}


{{NLM content}}
{{NLM content}}
{{gene-9-stub}}
 
{{Transcription factors}}
[[Category:Transcription factors]]
[[Category:Transcription factors]]
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Revision as of 09:12, 18 October 2017

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Kruppel-like factor 4 (KLF4; gut-enriched Krüppel-like factor or GKLF) is a zinc-finger transcription factor, and it was first identified in 1996.[1] KLF4 is a member of the KLF family of transcription factors, which belongs to the relatively large family of SP1-like transcription factors.[2][3][4] KLF4 is involved in the regulation of proliferation, differentiation, apoptosis and somatic cell reprogramming. Evidence also suggests that KLF4 is a tumor suppressor in certain cancers, including Colorectal cancer.[5] It has three C2H2-zinc fingers at its carboxyl terminus that are closely related to another KLF, KLF2.[3] It has two nuclear localization sequences that signals it to localize to the nucleus.[6] In embryonic stem cells (ESCs), KLF4 has been demonstrated to be a good indicator of stem-like capacity. It is suggested that the same is true in mesenchymal stem cells (MSCs).

In humans, the protein is 513 amino acids with a predicted molecular weight of approximately 55kDa and is encoded by the KLF4 gene.[7]. The KLF4 gene is conserved in chimpanzee, rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, and frog.[8]

Interactions

KLF4 can activate transcription by interacting via it N-terminus with specific transcriptional co-activators, such as p300-CBP coactivator family.[9][10][11] Transcriptional repression by KLF4 is carried out by KLF4 competing with an activator for binding to a target DNA sequence (9-12).[12][13][14][15] KLF4 has been shown to interact with CREB-binding protein.[16]

It was found that the transcription factor Klf4 present at the promoter of an enzymatic subunit of telomerase (TERT), where it formed a complex with β-catenin. Klf4 was required for accumulation of β-catenin at the Tert promoter but was unable to stimulate Tert expression in the absence of β-catenin.[17]

Function

KLF4 has diverse functions, and has been garnering attention in recent years because some of its functions are apparently contradicting, but mainly since the discovery of its integral role as one of four key factors that are essential for inducing pluripotent stem cells.[18][19] KLF4 is highly expressed in non-dividing cells and its overexpression induces cell cycle arrest.[1][20][21][22][23] KLF4 is particularly important in preventing cell division when the DNA is damaged.[20][22][23][24] KLF4 is also important in regulating centrosome number and chromosome number (genetic stability),[25][26][27] and in promoting cell survival. [28][29][30][31][32][33] However, some studies have revealed that under certain conditions KLF4 may switch its role from pro-cell survival to pro-cell death.[32][34][35][36]

KLF4 is expressed in the cells that are non-dividing and are terminally differentiated in the intestinal epithelium, where KLF4 is important in the regulation of intestinal epithelium homeostasis (terminal cell differentiation and proper localization of the different intestinal epithelium cell types).[37][38][39][40] In the intestinal epithelium, KLF4 is an important regulator of Wnt signaling pathway genes of genes regulating differentiation.[40]

KLF4 is expressed in a variety of tissues and organs such as: the cornea where it is required for epithelial barrier function[41][42] and is a regulator of genes required for corneal homeostasis;[43] the skin where it is required for the development of skin permeability barrier function;[44][45][46] the bone and teeth tissues where it regulates normal skeletal development;[47][48][49][50] epithelial cell of the mouse male and female reproductive tract[51] where in the males it is important for proper spermatogenesis;[52][53][54] vascular endothelial cells[55] where it is critical in preventing vascular leakage in response to inflammatory stimuli;[56] white blood cells where it mediates inflammatory responses cellular differentiation[57][58][59][60] and proliferation;[60][61] the kidneys where it is involved in the differentiation of embryonic stem cells and induced pluripotent stem (iPS) cells to renal lineage in vitro[62] and its dysregulation has been linked to some renal pathologies.[63][64][65]

Roles in diseases

Several lines of evidence have shown that KLF4 role in disease is context dependent where under certain conditions it may play one role and under different conditions it may assume a complete opposite role.

KLF4 is an anti-tumorigenic factor and its expression is often lost in various human cancer types, such as Colorectal cancer,[66] gastric cancer,[67] esophageal squamous cell carcinoma,[68] intestinal cancer,[69] prostate cancer,[70] bladder cancer[71] and lung cancer.[72]

However, in some cancer types KLF4 may act as a tumor promoter where increased KLF4 expression has been reported, such as in oral squamous cell carcinoma[73] and in primary breast ductal carcinoma.[74] Also, overexpression of KLF4 in skin resulted in hyperplasia and dysplasia,[75] which lead to the development of squamous cell carcinoma.[76] Similar finding in esophageal epithelium was observed, where overexpression of KLF4 resulted in increased inflammation that eventually lead to the development of esophageal squamous cell cancer in mice.[77]

The role of KLF4 in Epithelial–mesenchymal transition (EMT) is also controversial. It was shown to stimulate EMT in some systems by promoting/maintaining stemness of cancer cells, as is the case in pancreatic cancer,[78][79][80] head and neck cancer,[81] endometrial cancer,[82] nasopharyngeal cancer,[83] prostate cancer[84] and non-small lung cancer.[85] Under conditions of TGFβ-induced EMT KLF4 was shown to suppress EMT in the same systems where it was shown to promote EMT, such as prostate cancer[86] and pancreatic cancer.[87] Additionally, KLF4 was shown to suppress EMT in epidermal cancer,[88] breast cancer,[89] lung cancer,[90] cisplatin-resistant nasopharyngeal carcinoma cells,[91] and in hepatocellular carcinoma cells.[92]

KLF4 plays an important role in several vascular diseases where it was shown to regulate vascular inflammation by controlling macrophage polarization[93] and plaque formation in atherosclerosis.[94][95][96] It up-regulates Apolipoprotein E, which is an anti-atherosclerotic factor.[95] It is also involved in the regulation of angiogenesis. It may suppress angiogenesis by regulating NOTCH1 activity,[97] while in the central nervous system its overexpression leads to vascular dysplasia.[98]

KLF4 may promote inflammation by mediating NF-κB-dependent inflammatory pathway such as in macrophages,[99] esophageal epithelium[100] and in chemically-induced acute colitis in mice.[101] However, KLF4 may also suppress the activation of inflammatory signaling such as in endothelial cells in response to pro-inflammatory stimuli.[102]

KLF4 is essential for the cellular response to DNA damage. It is required for preventing cell cycle entry into mitosis following γ-irradiation-induced DNA damage,[103][104] in promoting DNA repair mechanisms (20) and in preventing the irradiated cell from undergoing programmed cell death (apoptosis) (23,25,26).[105][106][107] In one study, the in vivo importance of KLF4 in response to γ-irradiation-induced DNA damage was revealed where deletion of KLF4 specifically from the intestinal epithelium in mice lead to inability of the intestinal epithelium to regenerate and resulting in increased mortality of these mice.[107]

Importance in Stem cells

Takahashi and Yamanaka were the first identify KLF4 as one of four factors that are required to induce mouse embryonic and adult fibroblasts into pluripotent stem cells (iPS).[108] This was also found to be true for adult human fibroblasts.[109] Since 2006 up to today, the work on clinically relevant research in stem cells and stem cell induction, has increased dramatically (more than 10,000 research articles, as compared to about 60 between years 1900 to 2005). In vivo functional studies on the role of KLF4 in stem cells are rare. Recently a group investigated the role of KLF4 in a particular population of intestinal stem cells, the Bmi1+ stem cells.[110] This population of intestinal stem cells: are normally slow dividing, are known to be resistant to radiation injury, and are the ones responsible for intestinal epithelium regeneration following radiation injury.[111] The study showed that in the intestine, following -irradiation-induced DNA damage, KLF4 may regulate epithelial regeneration by modulating the fate of Bmi1+ stem cells themselves, and consequently the development of BMI1+ intestinal stem cell-derived lineage.[112]

See also

Notes


References

  1. ↑ 1.0 1.1 Shields JM, Christy RJ, Yang VW (August 1996). "Identification and characterization of a gene encoding a gut-enriched Krüppel-like factor expressed during growth arrest". The Journal of Biological Chemistry. 271 (33): 20009–17. PMID 8702718.
  2. ↑ Black AR, Black JD, Azizkhan-Clifford J (August 2001). "Sp1 and krüppel-like factor family of transcription factors in cell growth regulation and cancer". Journal of Cellular Physiology. 188 (2): 143–60. doi:10.1002/jcp.1111. PMID 11424081.
  3. ↑ 3.0 3.1 Dang DT, Pevsner J, Yang VW (November 2000). "The biology of the mammalian Krüppel-like family of transcription factors". The International Journal of Biochemistry & Cell Biology. 32 (11–12): 1103–21. PMID 11137451.
  4. ↑ Kaczynski J, Cook T, Urrutia R (2003). "Sp1- and Krüppel-like transcription factors". Genome Biology. 4 (2): 206. PMID 12620113.
  5. ↑ El-Karim EA, Hagos EG, Ghaleb AM, Yu B, Yang VW (August 2013). "Krüppel-like factor 4 regulates genetic stability in mouse embryonic fibroblasts". Molecular Cancer. 12: 89. doi:10.1186/1476-4598-12-89.
  6. ↑ Shields JM, Yang VW (July 1997). "Two potent nuclear localization signals in the gut-enriched Krüppel-like factor define a subfamily of closely related Krüppel proteins". The Journal of Biological Chemistry. 272 (29): 18504–7. PMID 9218496.
  7. ↑ "Entrez Gene: KLF4 Kruppel-like factor 4 (gut)".
  8. ↑ "Kruppel-like factor 4".
  9. ↑ Garrett-Sinha LA, Eberspaecher H, Seldin MF, de Crombrugghe B (December 1996). "A gene for a novel zinc-finger protein expressed in differentiated epithelial cells and transiently in certain mesenchymal cells". The Journal of Biological Chemistry. 271 (49): 31384–90. PMID 8940147.
  10. ↑ Geiman DE, Ton-That H, Johnson JM, Yang VW (March 2000). "Transactivation and growth suppression by the gut-enriched Krüppel-like factor (Krüppel-like factor 4) are dependent on acidic amino acid residues and protein-protein interaction". Nucleic Acids Research. 28 (5): 1106–13. PMID 10666450.
  11. ↑ Evans PM, Zhang W, Chen X, Yang J, Bhakat KK, Liu C (November 2007). "Kruppel-like factor 4 is acetylated by p300 and regulates gene transcription via modulation of histone acetylation". The Journal of Biological Chemistry. 282 (47): 33994–4002. doi:10.1074/jbc.M701847200. PMID 17908689.
  12. ↑ Zhang W, Shields JM, Sogawa K, Fujii-Kuriyama Y, Yang VW (July 1998). "The gut-enriched Krüppel-like factor suppresses the activity of the CYP1A1 promoter in an Sp1-dependent fashion". The Journal of Biological Chemistry. 273 (28): 17917–25. PMID 9651398.
  13. ↑ Ai W, Liu Y, Langlois M, Wang TC (March 2004). "Kruppel-like factor 4 (KLF4) represses histidine decarboxylase gene expression through an upstream Sp1 site and downstream gastrin responsive elements". The Journal of Biological Chemistry. 279 (10): 8684–93. doi:10.1074/jbc.M308278200. PMID 14670968.
  14. ↑ Feinberg MW, Cao Z, Wara AK, Lebedeva MA, Senbanerjee S, Jain MK (November 2005). "Kruppel-like factor 4 is a mediator of proinflammatory signaling in macrophages". The Journal of Biological Chemistry. 280 (46): 38247–58. doi:10.1074/jbc.M509378200. PMID 16169848.
  15. ↑ Kanai M, Wei D, Li Q, Jia Z, Ajani J, Le X, Yao J, Xie K (November 2006). "Loss of Krüppel-like factor 4 expression contributes to Sp1 overexpression and human gastric cancer development and progression". Clinical Cancer Research. 12 (21): 6395–402. doi:10.1158/1078-0432.CCR-06-1034. PMID 17085651.
  16. ↑ Geiman DE, Ton-That H, Johnson JM, Yang VW (March 2000). "Transactivation and growth suppression by the gut-enriched Krüppel-like factor (Krüppel-like factor 4) are dependent on acidic amino acid residues and protein-protein interaction". Nucleic Acids Research. 28 (5): 1106–13. doi:10.1093/nar/28.5.1106. PMC 102607. PMID 10666450.
  17. ↑ Hoffmeyer K, Raggioli A, Rudloff S, Anton R, Hierholzer A, Del Valle I, Hein K, Vogt R, Kemler R (June 2012). "Wnt/β-catenin signaling regulates telomerase in stem cells and cancer cells". Science. 336 (6088): 1549–54. doi:10.1126/science.1218370. PMID 22723415.
  18. ↑ Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (November 2007). "Induction of pluripotent stem cells from adult human fibroblasts by defined factors". Cell. 131 (5): 861–72. doi:10.1016/j.cell.2007.11.019. PMID 18035408.
  19. ↑ Takahashi K, Yamanaka S (August 2006). "Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors". Cell. 126 (4): 663–76. doi:10.1016/j.cell.2006.07.024. PMID 16904174.
  20. ↑ 20.0 20.1 Chen X, Johns DC, Geiman DE, Marban E, Dang DT, Hamlin G, Sun R, Yang VW (August 2001). "Krüppel-like factor 4 (gut-enriched Krüppel-like factor) inhibits cell proliferation by blocking G1/S progression of the cell cycle". The Journal of Biological Chemistry. 276 (32): 30423–8. doi:10.1074/jbc.M101194200. PMID 11390382.
  21. ↑ Dang DT, Chen X, Feng J, Torbenson M, Dang LH, Yang VW (May 2003). "Overexpression of Krüppel-like factor 4 in the human colon cancer cell line RKO leads to reduced tumorigenecity". Oncogene. 22 (22): 3424–30. doi:10.1038/sj.onc.1206413. PMID 12776194.
  22. ↑ 22.0 22.1 Yoon HS, Yang VW (February 2004). "Requirement of Krüppel-like factor 4 in preventing entry into mitosis following DNA damage". The Journal of Biological Chemistry. 279 (6): 5035–41. doi:10.1074/jbc.M307631200. PMID 14627709.
  23. ↑ 23.0 23.1 Yoon HS, Chen X, Yang VW (January 2003). "Kruppel-like factor 4 mediates p53-dependent G1/S cell cycle arrest in response to DNA damage". The Journal of Biological Chemistry. 278 (4): 2101–5. doi:10.1074/jbc.M211027200. PMID 12427745.
  24. ↑ Yoon HS, Ghaleb AM, Nandan MO, Hisamuddin IM, Dalton WB, Yang VW (June 2005). "Krüppel-like factor 4 prevents centrosome amplification following gamma-irradiation-induced DNA damage". Oncogene. 24 (25): 4017–25. doi:10.1038/sj.onc.1208576. PMID 15806166.
  25. ↑ El-Karim EA, Hagos EG, Ghaleb AM, Yu B, Yang VW (August 2013). "Krüppel-like factor 4 regulates genetic stability in mouse embryonic fibroblasts". Molecular Cancer. 12: 89. doi:10.1186/1476-4598-12-89. PMID 23919723.
  26. ↑ Hagos EG, Ghaleb AM, Dalton WB, Bialkowska AB, Yang VW (March 2009). "Mouse embryonic fibroblasts null for the Krüppel-like factor 4 gene are genetically unstable". Oncogene. 28 (9): 1197–205. doi:10.1038/onc.2008.465. PMID 19137014.
  27. ↑ Ghaleb AM, Elkarim EA, Bialkowska AB, Yang VW (April 2016). "KLF4 Suppresses Tumor Formation in Genetic and Pharmacological Mouse Models of Colonic Tumorigenesis". Molecular Cancer Research. 14 (4): 385–96. doi:10.1158/1541-7786.MCR-15-0410. PMID 26839262.
  28. ↑ Rowland BD, Bernards R, Peeper DS (November 2005). "The KLF4 tumour suppressor is a transcriptional repressor of p53 that acts as a context-dependent oncogene". Nature Cell Biology. 7 (11): 1074–82. doi:10.1038/ncb1314. PMID 16244670.
  29. ↑ Yang Y, Goldstein BG, Chao HH, Katz JP (November 2005). "KLF4 and KLF5 regulate proliferation, apoptosis and invasion in esophageal cancer cells". Cancer Biology & Therapy. 4 (11): 1216–21. PMID 16357509.
  30. ↑ McConnell BB, Ghaleb AM, Nandan MO, Yang VW (June 2007). "The diverse functions of Krüppel-like factors 4 and 5 in epithelial biology and pathobiology". BioEssays. 29 (6): 549–57. doi:10.1002/bies.20581. PMID 17508399.
  31. ↑ Talmasov D, Xinjun Z, Yu B, Nandan MO, Bialkowska AB, Elkarim E, Kuruvilla J, Yang VW, Ghaleb AM (January 2015). "Krüppel-like factor 4 is a radioprotective factor for the intestine following γ-radiation-induced gut injury in mice". American Journal of Physiology. Gastrointestinal and Liver Physiology. 308 (2): G121–38. doi:10.1152/ajpgi.00080.2014. PMID 25414097.
  32. ↑ 32.0 32.1 Wang B, Zhao MZ, Cui NP, Lin DD, Zhang AY, Qin Y, Liu CY, Yan WT, Shi JH, Chen BP (2 March 2015). "Krüppel-like factor 4 induces apoptosis and inhibits tumorigenic progression in SK-BR-3 breast cancer cells". FEBS Open Bio. 5: 147–54. doi:10.1016/j.fob.2015.02.003. PMID 25834779.
  33. ↑ Kuruvilla JG, Kim CK, Ghaleb AM, Bialkowska AB, Kuo CJ, Yang VW (June 2016). "Krüppel-like Factor 4 Modulates Development of BMI1(+) Intestinal Stem Cell-Derived Lineage Following γ-Radiation-Induced Gut Injury in Mice". Stem Cell Reports. 6 (6): 815–24. doi:10.1016/j.stemcr.2016.04.014. PMID 27237377.
  34. ↑ Liu MD, Liu Y, Liu JW, Zhang HL, Xiao XZ (December 2007). "[Effect of Krüppel-like factor 4 overexpression on heat stress-induced apoptosis of Raw264.7 macrophages]". Zhong Nan Da Xue Xue Bao. Yi Xue Ban = Journal of Central South University. Medical Sciences. 32 (6): 1002–6. PMID 18182717.
  35. ↑ Li Z, Zhao J, Li Q, Yang W, Song Q, Li W, Liu J (November 2010). "KLF4 promotes hydrogen-peroxide-induced apoptosis of chronic myeloid leukemia cells involving the bcl-2/bax pathway". Cell Stress & Chaperones. 15 (6): 905–12. doi:10.1007/s12192-010-0199-5. PMID 20401760.
  36. ↑ Whitlock NC, Bahn JH, Lee SH, Eling TE, Baek SJ (January 2011). "Resveratrol-induced apoptosis is mediated by early growth response-1, Krüppel-like factor 4, and activating transcription factor 3". Cancer Prevention Research. 4 (1): 116–27. doi:10.1158/1940-6207.CAPR-10-0218. PMID 21205742.
  37. ↑ Katz JP, Perreault N, Goldstein BG, Lee CS, Labosky PA, Yang VW, Kaestner KH (June 2002). "The zinc-finger transcription factor Klf4 is required for terminal differentiation of goblet cells in the colon". Development. 129 (11): 2619–28. PMID 12015290.
  38. ↑ Choi BJ, Cho YG, Song JW, Kim CJ, Kim SY, Nam SW, Yoo NJ, Lee JY, Park WS (2006). "Altered expression of the KLF4 in colorectal cancers". Pathology, Research and Practice. 202 (8): 585–9. doi:10.1016/j.prp.2006.05.001. PMID 16814484.
  39. ↑ Ghaleb AM, McConnell BB, Nandan MO, Katz JP, Kaestner KH, Yang VW (August 2007). "Haploinsufficiency of Krüppel-like factor 4 promotes adenomatous polyposis coli dependent intestinal tumorigenesis". Cancer Research. 67 (15): 7147–54. doi:10.1158/0008-5472.CAN-07-1302. PMID 17671182.
  40. ↑ 40.0 40.1 Ghaleb AM, McConnell BB, Kaestner KH, Yang VW (January 2011). "Altered intestinal epithelial homeostasis in mice with intestine-specific deletion of the Krüppel-like factor 4 gene". Developmental Biology. 349 (2): 310–20. doi:10.1016/j.ydbio.2010.11.001. PMID 21070761.
  41. ↑ Norman B, Davis J, Piatigorsky J (February 2004). "Postnatal gene expression in the normal mouse cornea by SAGE". Investigative Ophthalmology & Visual Science. 45 (2): 429–40. PMID 14744882.
  42. ↑ Swamynathan S, Kenchegowda D, Piatigorsky J, Swamynathan S (March 2011). "Regulation of corneal epithelial barrier function by Kruppel-like transcription factor 4". Investigative Ophthalmology & Visual Science. 52 (3): 1762–9. doi:10.1167/iovs.10-6134. PMID 21051695.
  43. ↑ Swamynathan SK, Davis J, Piatigorsky J (August 2008). "Identification of candidate Klf4 target genes reveals the molecular basis of the diverse regulatory roles of Klf4 in the mouse cornea". Investigative Ophthalmology & Visual Science. 49 (8): 3360–70. doi:10.1167/iovs.08-1811. PMID 18469187.
  44. ↑ Segre JA, Bauer C, Fuchs E (August 1999). "Klf4 is a transcription factor required for establishing the barrier function of the skin". Nature Genetics. 22 (4): 356–60. doi:10.1038/11926. PMID 10431239.
  45. ↑ Jaubert J, Cheng J, Segre JA (June 2003). "Ectopic expression of kruppel like factor 4 (Klf4) accelerates formation of the epidermal permeability barrier". Development. 130 (12): 2767–77. PMID 12736219.
  46. ↑ Li J, Zheng H, Yu F, Yu T, Liu C, Huang S, Wang TC, Ai W (June 2012). "Deficiency of the Kruppel-like factor KLF4 correlates with increased cell proliferation and enhanced skin tumorigenesis". Carcinogenesis. 33 (6): 1239–46. doi:10.1093/carcin/bgs143. PMID 22491752.
  47. ↑ Michikami I, Fukushi T, Tanaka M, Egusa H, Maeda Y, Ooshima T, Wakisaka S, Abe M (February 2012). "Krüppel-like factor 4 regulates membranous and endochondral ossification". Experimental Cell Research. 318 (4): 311–25. doi:10.1016/j.yexcr.2011.12.013. PMID 22206865.
  48. ↑ Fujikawa J, Tanaka M, Itoh S, Fukushi T, Kurisu K, Takeuchi Y, Morisaki I, Wakisaka S, Abe M (October 2014). "Kruppel-like factor 4 expression in osteoblasts represses osteoblast-dependent osteoclast maturation". Cell and Tissue Research. 358 (1): 177–87. doi:10.1007/s00441-014-1931-8. PMID 24927920.
  49. ↑ Kim JH, Kim K, Youn BU, Lee J, Kim I, Shin HI, Akiyama H, Choi Y, Kim N (March 2014). "Kruppel-like factor 4 attenuates osteoblast formation, function, and cross talk with osteoclasts". The Journal of Cell Biology. 204 (6): 1063–74. doi:10.1083/jcb.201308102. PMID 24616223.
  50. ↑ Chen Z, Couble ML, Mouterfi N, Magloire H, Chen Z, Bleicher F (May 2009). "Spatial and temporal expression of KLF4 and KLF5 during murine tooth development". Archives of Oral Biology. 54 (5): 403–11. doi:10.1016/j.archoralbio.2009.02.003. PMID 19268913.
  51. ↑ Godmann M, Kosan C, Behr R (April 2010). "Krüppel-like factor 4 is widely expressed in the mouse male and female reproductive tract and responds as an immediate early gene to activation of the protein kinase A in TM4 Sertoli cells". Reproduction. 139 (4): 771–82. doi:10.1530/REP-09-0531. PMID 20051481.
  52. ↑ Behr R, Kaestner KH (July 2002). "Developmental and cell type-specific expression of the zinc finger transcription factor Krüppel-like factor 4 (Klf4) in postnatal mouse testis". Mechanisms of Development. 115 (1–2): 167–9. PMID 12049784.
  53. ↑ Sze KL, Lee WM, Lui WY (February 2008). "Expression of CLMP, a novel tight junction protein, is mediated via the interaction of GATA with the Kruppel family proteins, KLF4 and Sp1, in mouse TM4 Sertoli cells". Journal of Cellular Physiology. 214 (2): 334–44. doi:10.1002/jcp.21201. PMID 17620326.
  54. ↑ Godmann M, Katz JP, Guillou F, Simoni M, Kaestner KH, Behr R (March 2008). "Krüppel-like factor 4 is involved in functional differentiation of testicular Sertoli cells". Developmental Biology. 315 (2): 552–66. doi:10.1016/j.ydbio.2007.12.018. PMID 18243172.
  55. ↑ Hamik A, Lin Z, Kumar A, Balcells M, Sinha S, Katz J, Feinberg MW, Gerzsten RE, Edelman ER, Jain MK (May 2007). "Kruppel-like factor 4 regulates endothelial inflammation". The Journal of Biological Chemistry. 282 (18): 13769–79. doi:10.1074/jbc.M700078200. PMID 17339326.
  56. ↑ Cowan CE, Kohler EE, Dugan TA, Mirza MK, Malik AB, Wary KK (October 2010). "Kruppel-like factor-4 transcriptionally regulates VE-cadherin expression and endothelial barrier function". Circulation Research. 107 (8): 959–66. doi:10.1161/CIRCRESAHA.110.219592. PMID 20724706.
  57. ↑ Zhang P, Basu P, Redmond LC, Morris PE, Rupon JW, Ginder GD, Lloyd JA. "A functional screen for Krüppel-like factors that regulate the human gamma-globin gene through the CACCC promoter element". Blood Cells, Molecules & Diseases. 35 (2): 227–35. doi:10.1016/j.bcmd.2005.04.009. PMID 16023392.
  58. ↑ Liu J, Zhang H, Liu Y, Wang K, Feng Y, Liu M, Xiao X (October 2007). "KLF4 regulates the expression of interleukin-10 in RAW264.7 macrophages". Biochemical and Biophysical Research Communications. 362 (3): 575–81. doi:10.1016/j.bbrc.2007.07.157. PMID 17719562.
  59. ↑ Feinberg MW, Wara AK, Cao Z, Lebedeva MA, Rosenbauer F, Iwasaki H, Hirai H, Katz JP, Haspel RL, Gray S, Akashi K, Segre J, Kaestner KH, Tenen DG, Jain MK (September 2007). "The Kruppel-like factor KLF4 is a critical regulator of monocyte differentiation". The EMBO Journal. 26 (18): 4138–48. doi:10.1038/sj.emboj.7601824. PMID 17762869.
  60. ↑ 60.0 60.1 Klaewsongkram J, Yang Y, Golech S, Katz J, Kaestner KH, Weng NP (October 2007). "Krüppel-like factor 4 regulates B cell number and activation-induced B cell proliferation". Journal of Immunology. 179 (7): 4679–84. PMID 17878366.
  61. ↑ Yusuf I, Kharas MG, Chen J, Peralta RQ, Maruniak A, Sareen P, Yang VW, Kaestner KH, Fruman DA (May 2008). "KLF4 is a FOXO target gene that suppresses B cell proliferation". International Immunology. 20 (5): 671–81. doi:10.1093/intimm/dxn024. PMID 18375530.
  62. ↑ Song B, Niclis JC, Alikhan MA, Sakkal S, Sylvain A, Kerr PG, Laslett AL, Bernard CA, Ricardo SD (July 2011). "Generation of induced pluripotent stem cells from human kidney mesangial cells". Journal of the American Society of Nephrology. 22 (7): 1213–20. doi:10.1681/ASN.2010101022. PMID 21566060.
  63. ↑ Hayashi K, Sasamura H, Nakamura M, Sakamaki Y, Azegami T, Oguchi H, Tokuyama H, Wakino S, Hayashi K, Itoh H (October 2015). "Renin-angiotensin blockade resets podocyte epigenome through Kruppel-like Factor 4 and attenuates proteinuria". Kidney International. 88 (4): 745–53. doi:10.1038/ki.2015.178. PMID 26108068.
  64. ↑ Mreich E, Chen XM, Zaky A, Pollock CA, Saad S (June 2015). "The role of Krüppel-like factor 4 in transforming growth factor-β-induced inflammatory and fibrotic responses in human proximal tubule cells". Clinical and Experimental Pharmacology & Physiology. 42 (6): 680–6. doi:10.1111/1440-1681.12405. PMID 25882815.
  65. ↑ Chen WC, Lin HH, Tang MJ (September 2015). "Matrix-Stiffness-Regulated Inverse Expression of Krüppel-Like Factor 5 and Krüppel-Like Factor 4 in the Pathogenesis of Renal Fibrosis". The American Journal of Pathology. 185 (9): 2468–81. doi:10.1016/j.ajpath.2015.05.019. PMID 26212907.
  66. ↑ Zhao W, Hisamuddin IM, Nandan MO, Babbin BA, Lamb NE, Yang VW (January 2004). "Identification of Krüppel-like factor 4 as a potential tumor suppressor gene in colorectal cancer". Oncogene. 23 (2): 395–402. doi:10.1038/sj.onc.1207067. PMID 14724568.
  67. ↑ Wei D, Gong W, Kanai M, Schlunk C, Wang L, Yao JC, Wu TT, Huang S, Xie K (April 2005). "Drastic down-regulation of Krüppel-like factor 4 expression is critical in human gastric cancer development and progression". Cancer Research. 65 (7): 2746–54. doi:10.1158/0008-5472.CAN-04-3619. PMID 15805274.
  68. ↑ Yang Y, Goldstein BG, Chao HH, Katz JP (November 2005). "KLF4 and KLF5 regulate proliferation, apoptosis and invasion in esophageal cancer cells". Cancer Biology & Therapy. 4 (11): 1216–21. PMID 16357509.
  69. ↑ Ton-That H, Kaestner KH, Shields JM, Mahatanankoon CS, Yang VW (December 1997). "Expression of the gut-enriched Krüppel-like factor gene during development and intestinal tumorigenesis". FEBS Letters. 419 (2–3): 239–43. PMID 9428642.
  70. ↑ Schulz WA, Hatina J (January 2006). "Epigenetics of prostate cancer: beyond DNA methylation". Journal of Cellular and Molecular Medicine. 10 (1): 100–25. PMID 16563224.
  71. ↑ Ohnishi S, Ohnami S, Laub F, Aoki K, Suzuki K, Kanai Y, Haga K, Asaka M, Ramirez F, Yoshida T (August 2003). "Downregulation and growth inhibitory effect of epithelial-type Krüppel-like transcription factor KLF4, but not KLF5, in bladder cancer". Biochemical and Biophysical Research Communications. 308 (2): 251–6. PMID 12901861.
  72. ↑ Hu W, Hofstetter WL, Li H, Zhou Y, He Y, Pataer A, Wang L, Xie K, Swisher SG, Fang B (September 2009). "Putative tumor-suppressive function of Kruppel-like factor 4 in primary lung carcinoma". Clinical Cancer Research. 15 (18): 5688–95. doi:10.1158/1078-0432.CCR-09-0310. PMID 19737957.
  73. ↑ Foster KW, Ren S, Louro ID, Lobo-Ruppert SM, McKie-Bell P, Grizzle W, Hayes MR, Broker TR, Chow LT, Ruppert JM (June 1999). "Oncogene expression cloning by retroviral transduction of adenovirus E1A-immortalized rat kidney RK3E cells: transformation of a host with epithelial features by c-MYC and the zinc finger protein GKLF". Cell Growth & Differentiation. 10 (6): 423–34. PMID 10392904.
  74. ↑ Foster KW, Frost AR, McKie-Bell P, Lin CY, Engler JA, Grizzle WE, Ruppert JM (November 2000). "Increase of GKLF messenger RNA and protein expression during progression of breast cancer". Cancer Research. 60 (22): 6488–95. PMID 11103818.
  75. ↑ Foster KW, Liu Z, Nail CD, Li X, Fitzgerald TJ, Bailey SK, Frost AR, Louro ID, Townes TM, Paterson AJ, Kudlow JE, Lobo-Ruppert SM, Ruppert JM (February 2005). "Induction of KLF4 in basal keratinocytes blocks the proliferation-differentiation switch and initiates squamous epithelial dysplasia". Oncogene. 24 (9): 1491–500. doi:10.1038/sj.onc.1208307. PMID 15674344.
  76. ↑ Huang CC, Liu Z, Li X, Bailey SK, Nail CD, Foster KW, Frost AR, Ruppert JM, Lobo-Ruppert SM (December 2005). "KLF4 and PCNA identify stages of tumor initiation in a conditional model of cutaneous squamous epithelial neoplasia". Cancer Biology & Therapy. 4 (12): 1401–8. PMID 16357510.
  77. ↑ Tetreault MP, Wang ML, Yang Y, Travis J, Yu QC, Klein-Szanto AJ, Katz JP (December 2010). "Klf4 overexpression activates epithelial cytokines and inflammation-mediated esophageal squamous cell cancer in mice". Gastroenterology. 139 (6): 2124–2134.e9. doi:10.1053/j.gastro.2010.08.048. PMID 20816834.
  78. ↑ Pinho AV, Rooman I, Real FX (April 2011). "p53-dependent regulation of growth, epithelial-mesenchymal transition and stemness in normal pancreatic epithelial cells". Cell Cycle. 10 (8): 1312–21. doi:10.4161/cc.10.8.15363. PMID 21490434.
  79. ↑ Sureban SM, May R, Qu D, Weygant N, Chandrakesan P, Ali N, Lightfoot SA, Pantazis P, Rao CV, Postier RG, Houchen CW (9 September 2013). "DCLK1 regulates pluripotency and angiogenic factors via microRNA-dependent mechanisms in pancreatic cancer". PloS One. 8 (9): e73940. doi:10.1371/journal.pone.0073940. PMID 24040120.
  80. ↑ Wellner U, Schubert J, Burk UC, Schmalhofer O, Zhu F, Sonntag A, Waldvogel B, Vannier C, Darling D, zur Hausen A, Brunton VG, Morton J, Sansom O, Schüler J, Stemmler MP, Herzberger C, Hopt U, Keck T, Brabletz S, Brabletz T (December 2009). "The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs". Nature Cell Biology. 11 (12): 1487–95. doi:10.1038/ncb1998. PMID 19935649.
  81. ↑ Chen Z, Wang Y, Liu W, Zhao G, Lee S, Balogh A, Zou Y, Guo Y, Zhang Z, Gu W, Li C, Tigyi G, Yue J (19 August 2014). "Doxycycline inducible Krüppel-like factor 4 lentiviral vector mediates mesenchymal to epithelial transition in ovarian cancer cells". PloS One. 9 (8): e105331. doi:10.1371/journal.pone.0105331. PMID 25137052.
  82. ↑ Dong P, Kaneuchi M, Watari H, Hamada J, Sudo S, Ju J, Sakuragi N (August 2011). "MicroRNA-194 inhibits epithelial to mesenchymal transition of endometrial cancer cells by targeting oncogene BMI-1". Molecular Cancer. 10: 99. doi:10.1186/1476-4598-10-99. PMID 21851624.
  83. ↑ Wu A, Luo W, Zhang Q, Yang Z, Zhang G, Li S, Yao K (April 2013). "Aldehyde dehydrogenase 1, a functional marker for identifying cancer stem cells in human nasopharyngeal carcinoma". Cancer Letters. 330 (2): 181–9. doi:10.1016/j.canlet.2012.11.046. PMID 23220285.
  84. ↑ Ren D, Wang M, Guo W, Zhao X, Tu X, Huang S, Zou X, Peng X (April 2013). "Wild-type p53 suppresses the epithelial-mesenchymal transition and stemness in PC-3 prostate cancer cells by modulating miR‑145". International Journal of Oncology. 42 (4): 1473–81. doi:10.3892/ijo.2013.1825. PMID 23404342.
  85. ↑ Kumar M, Allison DF, Baranova NN, Wamsley JJ, Katz AJ, Bekiranov S, Jones DR, Mayo MW (2013). "NF-κB regulates mesenchymal transition for the induction of non-small cell lung cancer initiating cells". PloS One. 8 (7): e68597. doi:10.1371/journal.pone.0068597. PMID 23935876.
  86. ↑ Liu YN, Abou-Kheir W, Yin JJ, Fang L, Hynes P, Casey O, Hu D, Wan Y, Seng V, Sheppard-Tillman H, Martin P, Kelly K (March 2012). "Critical and reciprocal regulation of KLF4 and SLUG in transforming growth factor β-initiated prostate cancer epithelial-mesenchymal transition". Molecular and Cellular Biology. 32 (5): 941–53. doi:10.1128/MCB.06306-11. PMID 22203039.
  87. ↑ Ouyang H, Gore J, Deitz S, Korc M (September 2014). "microRNA-10b enhances pancreatic cancer cell invasion by suppressing TIP30 expression and promoting EGF and TGF-β actions". Oncogene. 33 (38): 4664–74. doi:10.1038/onc.2013.405. PMID 24096486.
  88. ↑ Mistry DS, Chen Y, Wang Y, Zhang K, Sen GL (December 2014). "SNAI2 controls the undifferentiated state of human epidermal progenitor cells". Stem Cells. 32 (12): 3209–18. doi:10.1002/stem.1809. PMID 25100569.
  89. ↑ Wang B, Zhao MZ, Cui NP, Lin DD, Zhang AY, Qin Y, Liu CY, Yan WT, Shi JH, Chen BP (2 March 2015). "Krüppel-like factor 4 induces apoptosis and inhibits tumorigenic progression in SK-BR-3 breast cancer cells". FEBS Open Bio. 5: 147–54. doi:10.1016/j.fob.2015.02.003. PMID 25834779.
  90. ↑ Liu S, Yang H, Chen Y, He B, Chen Q (2016). "Krüppel-Like Factor 4 Enhances Sensitivity of Cisplatin to Lung Cancer Cells and Inhibits Regulating Epithelial-to-Mesenchymal Transition". Oncology Research. 24 (2): 81–7. doi:10.3727/096504016X14597766487717. PMID 27296948.
  91. ↑ Zhang P, Hong H, Sun X, Jiang H, Ma S, Zhao S, Zhang M, Wang Z, Jiang C, Liu H (15 January 2016). "MicroRNA-10b regulates epithelial-mesenchymal transition by modulating KLF4/Notch1/E-cadherin in cisplatin-resistant nasopharyngeal carcinoma cells". American Journal of Cancer Research. 6 (2): 141–56. PMID 27186392.
  92. ↑ Li Q, Song W, Wang W, Yao S, Tian C, Cai X, Wang L (May 2016). "Suppression of epithelial-mesenchymal transition in hepatocellular carcinoma cells by Krüppel-like factor 4". Oncotarget. 7 (20): 29749–60. doi:10.18632/oncotarget.8831. PMID 27102441.
  93. ↑ Liao X, Sharma N, Kapadia F, Zhou G, Lu Y, Hong H, Paruchuri K, Mahabeleshwar GH, Dalmas E, Venteclef N, Flask CA, Kim J, Doreian BW, Lu KQ, Kaestner KH, Hamik A, Clément K, Jain MK (July 2011). "Krüppel-like factor 4 regulates macrophage polarization". The Journal of Clinical Investigation. 121 (7): 2736–49. doi:10.1172/JCI45444. PMID 21670502.
  94. ↑ Sharma N, Lu Y, Zhou G, Liao X, Kapil P, Anand P, Mahabeleshwar GH, Stamler JS, Jain MK (December 2012). "Myeloid Krüppel-like factor 4 deficiency augments atherogenesis in ApoE-/- mice--brief report". Arteriosclerosis, Thrombosis, and Vascular Biology. 32 (12): 2836–8. doi:10.1161/ATVBAHA.112.300471. PMID 23065827.
  95. ↑ 95.0 95.1 Stavri S, Simionescu M, Kardassis D, Gafencu AV (December 2015). "Krüppel-like factor 4 synergizes with CREB to increase the activity of apolipoprotein E gene promoter in macrophages". Biochemical and Biophysical Research Communications. 468 (1–2): 66–72. doi:10.1016/j.bbrc.2015.10.163. PMID 26546821.
  96. ↑ Hale AT, Longenecker CT, Jiang Y, Debanne SM, Labatto DE, Storer N, Hamik A, McComsey GA (August 2015). "HIV vasculopathy: role of mononuclear cell-associated Krüppel-like factors 2 and 4". Aids. 29 (13): 1643–50. doi:10.1097/QAD.0000000000000756. PMID 26372274.
  97. ↑ Hale AT, Tian H, Anih E, Recio FO, Shatat MA, Johnson T, Liao X, Ramirez-Bergeron DL, Proweller A, Ishikawa M, Hamik A (April 2014). "Endothelial Kruppel-like factor 4 regulates angiogenesis and the Notch signaling pathway". The Journal of Biological Chemistry. 289 (17): 12016–28. doi:10.1074/jbc.M113.530956. PMID 24599951.
  98. ↑ Cuttano R, Rudini N, Bravi L, Corada M, Giampietro C, Papa E, Morini MF, Maddaluno L, Baeyens N, Adams RH, Jain MK, Owens GK, Schwartz M, Lampugnani MG, Dejana E (November 2015). "KLF4 is a key determinant in the development and progression of cerebral cavernous malformations". EMBO Molecular Medicine. 8 (1): 6–24. doi:10.15252/emmm.201505433. PMID 26612856.
  99. ↑ Feinberg MW, Cao Z, Wara AK, Lebedeva MA, Senbanerjee S, Jain MK (November 2005). "Kruppel-like factor 4 is a mediator of proinflammatory signaling in macrophages". The Journal of Biological Chemistry. 280 (46): 38247–58. doi:10.1074/jbc.M509378200. PMID 16169848.
  100. ↑ Tetreault MP, Wang ML, Yang Y, Travis J, Yu QC, Klein-Szanto AJ, Katz JP (December 2010). "Klf4 overexpression activates epithelial cytokines and inflammation-mediated esophageal squamous cell cancer in mice". Gastroenterology. 139 (6): 2124–2134.e9. doi:10.1053/j.gastro.2010.08.048. PMID 20816834.
  101. ↑ Ghaleb AM, Laroui H, Merlin D, Yang VW (May 2014). "Genetic deletion of Klf4 in the mouse intestinal epithelium ameliorates dextran sodium sulfate-induced colitis by modulating the NF-κB pathway inflammatory response". Inflammatory Bowel Diseases. 20 (5): 811–20. doi:10.1097/MIB.0000000000000022. PMID 24681655.
  102. ↑ Hamik A, Lin Z, Kumar A, Balcells M, Sinha S, Katz J, Feinberg MW, Gerzsten RE, Edelman ER, Jain MK (May 2007). "Kruppel-like factor 4 regulates endothelial inflammation". The Journal of Biological Chemistry. 282 (18): 13769–79. doi:10.1074/jbc.M700078200. PMID 17339326.
  103. ↑ Yoon HS, Yang VW (February 2004). "Requirement of Krüppel-like factor 4 in preventing entry into mitosis following DNA damage". The Journal of Biological Chemistry. 279 (6): 5035–41. doi:10.1074/jbc.M307631200. PMID 14627709.
  104. ↑ Yoon HS, Chen X, Yang VW (January 2003). "Kruppel-like factor 4 mediates p53-dependent G1/S cell cycle arrest in response to DNA damage". The Journal of Biological Chemistry. 278 (4): 2101–5. doi:10.1074/jbc.M211027200. PMID 12427745.
  105. ↑ Rowland BD, Bernards R, Peeper DS (November 2005). "The KLF4 tumour suppressor is a transcriptional repressor of p53 that acts as a context-dependent oncogene". Nature Cell Biology. 7 (11): 1074–82. doi:10.1038/ncb1314. PMID 16244670.
  106. ↑ McConnell BB, Ghaleb AM, Nandan MO, Yang VW (June 2007). "The diverse functions of Krüppel-like factors 4 and 5 in epithelial biology and pathobiology". BioEssays. 29 (6): 549–57. doi:10.1002/bies.20581. PMID 17508399.
  107. ↑ 107.0 107.1 Talmasov D, Xinjun Z, Yu B, Nandan MO, Bialkowska AB, Elkarim E, Kuruvilla J, Yang VW, Ghaleb AM (January 2015). "Krüppel-like factor 4 is a radioprotective factor for the intestine following γ-radiation-induced gut injury in mice". American Journal of Physiology. Gastrointestinal and Liver Physiology. 308 (2): G121–38. doi:10.1152/ajpgi.00080.2014. PMID 25414097.
  108. ↑ Takahashi K, Yamanaka S (August 2006). "Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors". Cell. 126 (4): 663–76. doi:10.1016/j.cell.2006.07.024. PMID 16904174.
  109. ↑ Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (November 2007). "Induction of pluripotent stem cells from adult human fibroblasts by defined factors". Cell. 131 (5): 861–72. doi:10.1016/j.cell.2007.11.019. PMID 18035408.
  110. ↑ Kuruvilla JG, Kim CK, Ghaleb AM, Bialkowska AB, Kuo CJ, Yang VW (June 2016). "Krüppel-like Factor 4 Modulates Development of BMI1(+) Intestinal Stem Cell-Derived Lineage Following γ-Radiation-Induced Gut Injury in Mice". Stem Cell Reports. 6 (6): 815–24. doi:10.1016/j.stemcr.2016.04.014. PMID 27237377.
  111. ↑ Yan KS, Chia LA, Li X, Ootani A, Su J, Lee JY, Su N, Luo Y, Heilshorn SC, Amieva MR, Sangiorgi E, Capecchi MR, Kuo CJ (January 2012). "The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations". Proceedings of the National Academy of Sciences of the United States of America. 109 (2): 466–71. doi:10.1073/pnas.1118857109. PMID 22190486.
  112. ↑ Kuruvilla JG, Kim CK, Ghaleb AM, Bialkowska AB, Kuo CJ, Yang VW (June 2016). "Krüppel-like Factor 4 Modulates Development of BMI1(+) Intestinal Stem Cell-Derived Lineage Following γ-Radiation-Induced Gut Injury in Mice". Stem Cell Reports. 6 (6): 815–24. doi:10.1016/j.stemcr.2016.04.014. PMID 27237377.

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