DDIT4: Difference between revisions

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{{Infobox_gene}}
{{PBB_Controls
'''DNA-damage-inducible transcript 4 (DDIT4)''' protein also known as protein '''regulated in development and DNA damage response 1''' ('''REDD1''') is a [[protein]] that in humans is encoded by the ''DDIT4'' [[gene]].<ref name="Shoshani_2002">{{cite journal | vauthors = Shoshani T, Faerman A, Mett I, Zelin E, Tenne T, Gorodin S, Moshel Y, Elbaz S, Budanov A, Chajut A, Kalinski H, Kamer I, Rozen A, Mor O, Keshet E, Leshkowitz D, Einat P, Skaliter R, Feinstein E | title = Identification of a novel hypoxia-inducible factor 1-responsive gene, RTP801, involved in apoptosis | journal = Molecular and Cellular Biology | volume = 22 | issue = 7 | pages = 2283–93 | date = April 2002 | pmid = 11884613 | pmc = 133671 | doi = 10.1128/MCB.22.7.2283-2293.2002 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: DDIT4 DNA-damage-inducible transcript 4| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=54541| accessdate = }}</ref>
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| require_manual_inspection = no
| update_protein_box = yes
| update_summary = yes
| update_citations = yes
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Function ==
{{GNF_Protein_box
| image =
| image_source =
| PDB =
| Name = DNA-damage-inducible transcript 4
| HGNCid = 24944
| Symbol = DDIT4
| AltSymbols =; Dig2; FLJ20500; REDD-1; REDD1; RP11-442H21.1; RTP801
| OMIM = 607729
| ECnumber = 
| Homologene = 10400
| MGIid = 1921997
| GeneAtlas_image1 = PBB_GE_DDIT4_202887_s_at_tn.png
| Function =  
| Component =
| Process =
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 54541
    | Hs_Ensembl = ENSG00000168209
    | Hs_RefseqProtein = NP_061931
    | Hs_RefseqmRNA = NM_019058
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 10
    | Hs_GenLoc_start = 73703683
    | Hs_GenLoc_end = 73705803
    | Hs_Uniprot = 
    | Mm_EntrezGene = 74747
    | Mm_Ensembl = ENSMUSG00000020108
    | Mm_RefseqmRNA = NM_029083
    | Mm_RefseqProtein = NP_083359
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 10
    | Mm_GenLoc_start = 59345032
    | Mm_GenLoc_end = 59347127
    | Mm_Uniprot = 
  }}
}}
'''DNA-damage-inducible transcript 4''', also known as '''DDIT4''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: DDIT4 DNA-damage-inducible transcript 4| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=54541| accessdate = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
DDIT4 acts as a negative regulator of [[mTOR]],<ref>{{cite journal | vauthors = Sofer A, Lei K, Johannessen CM, Ellisen LW | title = Regulation of mTOR and cell growth in response to energy stress by REDD1 | journal = Molecular and Cellular Biology | volume = 25 | issue = 14 | pages = 5834–45 | date = July 2005 | pmid = 15988001 | doi = 10.1128/MCB.25.14.5834-5845.2005 | pmc=1168803}}</ref> a serine/threonine kinase that regulates a variety of cellular functions such as growth, proliferation and autophagy.<ref name="ReferenceA">{{cite journal | vauthors = Sato T, Nakashima A, Guo L, Coffman K, Tamanoi F | title = Single amino-acid changes that confer constitutive activation of mTOR are discovered in human cancer | journal = Oncogene | volume = 29 | issue = 18 | pages = 2746–52 | date = May 2010 | pmid = 20190810 | doi = 10.1038/onc.2010.28 | pmc=2953941}}</ref> In particular, upregulation of [[HIF1A|HIF-1]] in response to [[Tumor hypoxia|hypoxia]] upregulates DDIT4,<ref name="Shoshani_2002" /> leading to activation of [[Tuberous sclerosis protein|Tsc1/2]] via [[14-3-3 protein|14–3–3 shuttling]] <ref>{{cite journal | vauthors = DeYoung MP, Horak P, Sofer A, Sgroi D, Ellisen LW | title = Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling | journal = Genes & Development | volume = 22 | issue = 2 | pages = 239–51 | date = January 2008 | pmid = 18198340 | doi = 10.1101/gad.1617608 | pmc=2192757}}</ref> and subsequent downregulation of mTOR via [[Rheb]].<ref>{{cite journal | vauthors = Inoki K, Li Y, Xu T, Guan KL | title = Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling | journal = Genes & Development | volume = 17 | issue = 15 | pages = 1829–34 | date = August 2003 | pmid = 12869586 | doi = 10.1101/gad.1110003 | pmc=196227}}</ref> In addition to hypoxia, DDRT4 expression has also been shown to be activated by DNA damage<ref>{{cite journal | vauthors = Ellisen LW, Ramsayer KD, Johannessen CM, Yang A, Beppu H, Minda K, Oliner JD, McKeon F, Haber DA | title = REDD1, a developmentally regulated transcriptional target of p63 and p53, links p63 to regulation of reactive oxygen species | journal = Molecular Cell | volume = 10 | issue = 5 | pages = 995–1005 | date = November 2002 | pmid = 12453409 | doi = 10.1016/S1097-2765(02)00706-2 }}</ref> and energy stress.<ref>{{cite journal | vauthors = McGhee NK, Jefferson LS, Kimball SR | title = Elevated corticosterone associated with food deprivation upregulates expression in rat skeletal muscle of the mTORC1 repressor, REDD1 | journal = The Journal of Nutrition | volume = 139 | issue = 5 | date = May 2009 | pmid = 19297425 | doi = 10.3945/jn.108.099846 | pmc=2714387}}</ref>
{{PBB_Summary
| section_title =  
| summary_text =  
}}


==References==
In terms of cellular stress, DDIT4 was shown to be induced upon hair follicular damage as a result of loss of the vitamin D receptor. <ref>{{cite journal | vauthors = Hengguang Z, Rieger S, Abe K, Hewison M, Lisse T | title = DNA Damage-Inducible Transcript 4 Is an Innate Surveillant of Hair Follicular Stress in Vitamin D Receptor Knockout Mice and a Regulator of Wound Re-Epithelialization| journal = Int. J. Mol. Sci. | volume = 17 | issue = 12 | date = November 2016 | pmid = 27898044  | doi = 10.3390/ijms17121984 | pmc=5187784 }}</ref>  Thus, DDIT4 was shown to regulate both hair growth and wound re-epithelialization interacting via the vitamin D receptor pathway.
{{reflist|2}}
 
==Further reading==
 
{{refbegin | 2}}
 
{{PBB_Further_reading
== Clinical significance ==
| citations =  
 
*{{cite journal  | author=Ellisen LW |title=Growth control under stress: mTOR regulation through the REDD1-TSC pathway. |journal=Cell Cycle |volume=4 |issue= 11 |pages= 1500-02 |year= 2007 |pmid= 16258273 |doi= }}
Clinical interest in DDIT4 is based primarily on its effect on mTOR, which has been associated with aging<ref name=zoncu2010>{{cite journal | vauthors = Zoncu R, Efeyan A, Sabatini DM | title = mTOR: from growth signal integration to cancer, diabetes and ageing | journal = Nature Reviews Molecular Cell Biology | volume = 12 | issue = 1 | pages = 21–35 | date = January 2011 | pmid = 21157483 | doi = 10.1038/nrm3025 | pmc=3390257}}</ref> and linked with diseases such as [[tuberous sclerosis]], [[lymphangioleiomyomatosis]],<ref>{{cite journal | vauthors = Sarbassov DD, Ali SM, Sabatini DM | title = Growing roles for the mTOR pathway | journal = Current Opinion in Cell Biology | volume = 17 | issue = 6 | pages = 596–603 | date = December 2005 | pmid = 16226444 | doi = 10.1016/j.ceb.2005.09.009 }}</ref> [[Diabetes mellitus|diabetes]],<ref name=zoncu2010 /> and [[cancer]]. In particular, the overactivation of mTOR in many cancer types<ref name="ReferenceA"/> has led to the development of [[mTOR inhibitors]] for [[Chemotherapy|cancer treatment]].  DDIT4 has begun to receive attention in this regard via the diabetes drug [[Metformin]] which has been shown to reduce cancer risk and increase DDIT4 expression.<ref>{{cite journal | vauthors = Ben Sahra I, Regazzetti C, Robert G, Laurent K, Le Marchand-Brustel Y, Auberger P, Tanti JF, Giorgetti-Peraldi S, Bost F | title = Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1 | journal = Cancer Research | volume = 71 | issue = 13 | pages = 4366–72 | date = July 2011 | pmid = 21540236 | doi = 10.1158/0008-5472.CAN-10-1769 }}</ref>
*{{cite journal | author=Hartley JL, Temple GF, Brasch MA |title=DNA cloning using in vitro site-specific recombination. |journal=Genome Res. |volume=10 |issue= 11 |pages= 1788-95 |year= 2001 |pmid= 11076863 |doi= }}
 
*{{cite journal | author=Wiemann S, Weil B, Wellenreuther R, ''et al.'' |title=Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs. |journal=Genome Res. |volume=11 |issue= 3 |pages= 422-35 |year= 2001 |pmid= 11230166 |doi= 10.1101/gr.154701 }}
== See also ==
*{{cite journal  | author=Simpson JC, Wellenreuther R, Poustka A, ''et al.'' |title=Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing. |journal=EMBO Rep. |volume=1 |issue= 3 |pages= 287-92 |year= 2001 |pmid= 11256614 |doi= 10.1093/embo-reports/kvd058 }}
 
*{{cite journal  | author=Shoshani T, Faerman A, Mett I, ''et al.'' |title=Identification of a novel hypoxia-inducible factor 1-responsive gene, RTP801, involved in apoptosis. |journal=Mol. Cell. Biol. |volume=22 |issue= 7 |pages= 2283-93 |year= 2002 |pmid= 11884613 |doi=  }}
* [[HIF1A]]
*{{cite journal | author=Ellisen LW, Ramsayer KD, Johannessen CM, ''et al.'' |title=REDD1, a developmentally regulated transcriptional target of p63 and p53, links p63 to regulation of reactive oxygen species. |journal=Mol. Cell |volume=10 |issue= 5 |pages= 995-1005 |year= 2003 |pmid= 12453409 |doi= }}
* [[Tuberous sclerosis protein]]
*{{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 }}
* [[MTOR]]
*{{cite journal | author=Kim JR, Lee SR, Chung HJ, ''et al.'' |title=Identification of amyloid beta-peptide responsive genes by cDNA microarray technology: involvement of RTP801 in amyloid beta-peptide toxicity. |journal=Exp. Mol. Med. |volume=35 |issue= 5 |pages= 403-11 |year= 2004 |pmid= 14646594 |doi= }}
* [[14-3-3 protein]]
*{{cite journal | author=Brandenberger R, Wei H, Zhang S, ''et al.'' |title=Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation. |journal=Nat. Biotechnol. |volume=22 |issue= 6 |pages= 707-16 |year= 2005 |pmid= 15146197 |doi= 10.1038/nbt971 }}
* [[DDIT4L/ REDD2]]
*{{cite journal | author=Lee M, Bikram M, Oh S, ''et al.'' |title=Sp1-dependent regulation of the RTP801 promoter and its application to hypoxia-inducible VEGF plasmid for ischemic disease. |journal=Pharm. Res. |volume=21 |issue= 5 |pages= 736-41 |year= 2004 |pmid= 15180327 |doi= }}
{{clear}}
*{{cite journal | author=Wiemann S, Arlt D, Huber W, ''et al.'' |title=From ORFeome to biology: a functional genomics pipeline. |journal=Genome Res. |volume=14 |issue= 10B |pages= 2136-44 |year= 2004 |pmid= 15489336 |doi= 10.1101/gr.2576704 }}
== References ==
*{{cite journal | author=Schwarzer R, Tondera D, Arnold W, ''et al.'' |title=REDD1 integrates hypoxia-mediated survival signaling downstream of phosphatidylinositol 3-kinase. |journal=Oncogene |volume=24 |issue= 7 |pages= 1138-49 |year= 2005 |pmid= 15592522 |doi= 10.1038/sj.onc.1208236 }}
{{reflist|33em}}
*{{cite journal | author=Corradetti MN, Inoki K, Guan KL |title=The stress-inducted proteins RTP801 and RTP801L are negative regulators of the mammalian target of rapamycin pathway. |journal=J. Biol. Chem. |volume=280 |issue= 11 |pages= 9769-72 |year= 2005 |pmid= 15632201 |doi= 10.1074/jbc.C400557200 }}
 
*{{cite journal | author=Sofer A, Lei K, Johannessen CM, Ellisen LW |title=Regulation of mTOR and cell growth in response to energy stress by REDD1. |journal=Mol. Cell. Biol. |volume=25 |issue= 14 |pages= 5834-45 |year= 2005 |pmid= 15988001 |doi= 10.1128/MCB.25.14.5834-5845.2005 }}
== Further reading ==
*{{cite journal | author=Oh JH, Yang JO, Hahn Y, ''et al.'' |title=Transcriptome analysis of human gastric cancer. |journal=Mamm. Genome |volume=16 |issue= 12 |pages= 942-54 |year= 2006 |pmid= 16341674 |doi= 10.1007/s00335-005-0075-2 }}
{{refbegin|33em}}
*{{cite journal | author=Mehrle A, Rosenfelder H, Schupp I, ''et al.'' |title=The LIFEdb database in 2006. |journal=Nucleic Acids Res. |volume=34 |issue= Database issue |pages= D415-8 |year= 2006 |pmid= 16381901 |doi= 10.1093/nar/gkj139 }}
* {{cite journal | vauthors = Ellisen LW | title = Growth control under stress: mTOR regulation through the REDD1-TSC pathway | journal = Cell Cycle | volume = 4 | issue = 11 | pages = 1500–02 | date = November 2005 | pmid = 16258273 | doi = 10.4161/cc.4.11.2139 }}
*{{cite journal | author=Lim J, Hao T, Shaw C, ''et al.'' |title=A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration. |journal=Cell |volume=125 |issue= 4 |pages= 801-14 |year= 2006 |pmid= 16713569 |doi= 10.1016/j.cell.2006.03.032 }}
* {{cite journal | vauthors = Hartley JL, Temple GF, Brasch MA | title = DNA cloning using in vitro site-specific recombination | journal = Genome Research | volume = 10 | issue = 11 | pages = 1788–95 | date = November 2000 | pmid = 11076863 | pmc = 310948 | doi = 10.1101/gr.143000 }}
*{{cite journal | author=Malagelada C, Ryu EJ, Biswas SC, ''et al.'' |title=RTP801 is elevated in Parkinson brain substantia nigral neurons and mediates death in cellular models of Parkinson's disease by a mechanism involving mammalian target of rapamycin inactivation. |journal=J. Neurosci. |volume=26 |issue= 39 |pages= 9996-10005 |year= 2006 |pmid= 17005863 |doi= 10.1523/JNEUROSCI.3292-06.2006 }}
* {{cite journal | vauthors = Wiemann S, Weil B, Wellenreuther R, Gassenhuber J, Glassl S, Ansorge W, Böcher M, Blöcker H, Bauersachs S, Blum H, Lauber J, Düsterhöft A, Beyer A, Köhrer K, Strack N, Mewes HW, Ottenwälder B, Obermaier B, Tampe J, Heubner D, Wambutt R, Korn B, Klein M, Poustka A | title = Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs | journal = Genome Research | volume = 11 | issue = 3 | pages = 422–35 | date = March 2001 | pmid = 11230166 | pmc = 311072 | doi = 10.1101/gr.GR1547R }}
*{{cite journal  | author=Jin HO, An S, Lee HC, ''et al.'' |title=Hypoxic condition- and high cell density-induced expression of Redd1 is regulated by activation of hypoxia-inducible factor-1alpha and Sp1 through the phosphatidylinositol 3-kinase/Akt signaling pathway. |journal=Cell. Signal. |volume=19 |issue= 7 |pages= 1393-403 |year= 2007 |pmid= 17307335 |doi= 10.1016/j.cellsig.2006.12.014 }}
* {{cite journal | vauthors = Simpson JC, Wellenreuther R, Poustka A, Pepperkok R, Wiemann S | title = Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing | journal = EMBO Reports | volume = 1 | issue = 3 | pages = 287–92 | date = September 2000 | pmid = 11256614 | pmc = 1083732 | doi = 10.1093/embo-reports/kvd058 }}
}}
* {{cite journal | vauthors = Kim JR, Lee SR, Chung HJ, Kim S, Baek SH, Kim JH, Kim YS | title = Identification of amyloid beta-peptide responsive genes by cDNA microarray technology: involvement of RTP801 in amyloid beta-peptide toxicity | journal = Experimental & Molecular Medicine | volume = 35 | issue = 5 | pages = 403–11 | date = October 2003 | pmid = 14646594 | doi = 10.1038/emm.2003.53 }}
* {{cite journal | vauthors = Brandenberger R, Wei H, Zhang S, Lei S, Murage J, Fisk GJ, Li Y, Xu C, Fang R, Guegler K, Rao MS, Mandalam R, Lebkowski J, Stanton LW | title = Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation | journal = Nature Biotechnology | volume = 22 | issue = 6 | pages = 707–16 | date = June 2004 | pmid = 15146197 | doi = 10.1038/nbt971 }}
* {{cite journal | vauthors = Lee M, Bikram M, Oh S, Bull DA, Kim SW | title = Sp1-dependent regulation of the RTP801 promoter and its application to hypoxia-inducible VEGF plasmid for ischemic disease | journal = Pharmaceutical Research | volume = 21 | issue = 5 | pages = 736–41 | date = May 2004 | pmid = 15180327 | doi = 10.1023/B:PHAM.0000026421.09367.b3 }}
* {{cite journal | vauthors = Wiemann S, Arlt D, Huber W, Wellenreuther R, Schleeger S, Mehrle A, Bechtel S, Sauermann M, Korf U, Pepperkok R, Sültmann H, Poustka A | title = From ORFeome to biology: a functional genomics pipeline | journal = Genome Research | volume = 14 | issue = 10B | pages = 2136–44 | date = October 2004 | pmid = 15489336 | pmc = 528930 | doi = 10.1101/gr.2576704 }}
* {{cite journal | vauthors = Schwarzer R, Tondera D, Arnold W, Giese K, Klippel A, Kaufmann J | title = REDD1 integrates hypoxia-mediated survival signaling downstream of phosphatidylinositol 3-kinase | journal = Oncogene | volume = 24 | issue = 7 | pages = 1138–49 | date = February 2005 | pmid = 15592522 | doi = 10.1038/sj.onc.1208236 }}
* {{cite journal | vauthors = Corradetti MN, Inoki K, Guan KL | title = The stress-inducted proteins RTP801 and RTP801L are negative regulators of the mammalian target of rapamycin pathway | journal = The Journal of Biological Chemistry | volume = 280 | issue = 11 | pages = 9769–72 | date = March 2005 | pmid = 15632201 | doi = 10.1074/jbc.C400557200 }}
* {{cite journal | vauthors = Sofer A, Lei K, Johannessen CM, Ellisen LW | title = Regulation of mTOR and cell growth in response to energy stress by REDD1 | journal = Molecular and Cellular Biology | volume = 25 | issue = 14 | pages = 5834–45 | date = July 2005 | pmid = 15988001 | pmc = 1168803 | doi = 10.1128/MCB.25.14.5834-5845.2005 }}
* {{cite journal | vauthors = Oh JH, Yang JO, Hahn Y, Kim MR, Byun SS, Jeon YJ, Kim JM, Song KS, Noh SM, Kim S, Yoo HS, Kim YS, Kim NS | title = Transcriptome analysis of human gastric cancer | journal = Mammalian Genome | volume = 16 | issue = 12 | pages = 942–54 | date = December 2005 | pmid = 16341674 | doi = 10.1007/s00335-005-0075-2 }}
* {{cite journal | vauthors = Mehrle A, Rosenfelder H, Schupp I, del Val C, Arlt D, Hahne F, Bechtel S, Simpson J, Hofmann O, Hide W, Glatting KH, Huber W, Pepperkok R, Poustka A, Wiemann S | title = The LIFEdb database in 2006 | journal = Nucleic Acids Research | volume = 34 | issue = Database issue | pages = D415-8 | date = January 2006 | pmid = 16381901 | pmc = 1347501 | doi = 10.1093/nar/gkj139 }}
* {{cite journal | vauthors = Lim J, Hao T, Shaw C, Patel AJ, Szabó G, Rual JF, Fisk CJ, Li N, Smolyar A, Hill DE, Barabási AL, Vidal M, Zoghbi HY | title = A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration | journal = Cell | volume = 125 | issue = 4 | pages = 801–14 | date = May 2006 | pmid = 16713569 | doi = 10.1016/j.cell.2006.03.032 }}
* {{cite journal | vauthors = Malagelada C, Ryu EJ, Biswas SC, Jackson-Lewis V, Greene LA | title = RTP801 is elevated in Parkinson brain substantia nigral neurons and mediates death in cellular models of Parkinson's disease by a mechanism involving mammalian target of rapamycin inactivation | journal = The Journal of Neuroscience | volume = 26 | issue = 39 | pages = 9996–10005 | date = September 2006 | pmid = 17005863 | doi = 10.1523/JNEUROSCI.3292-06.2006 }}
* {{cite journal | vauthors = Jin HO, An S, Lee HC, Woo SH, Seo SK, Choe TB, Yoo DH, Lee SB, Um HD, Lee SJ, Park MJ, Kim JI, Hong SI, Rhee CH, Park IC | display-authors = 6 | title = Hypoxic condition- and high cell density-induced expression of Redd1 is regulated by activation of hypoxia-inducible factor-1alpha and Sp1 through the phosphatidylinositol 3-kinase/Akt signaling pathway | journal = Cellular Signalling | volume = 19 | issue = 7 | pages = 1393–403 | date = July 2007 | pmid = 17307335 | doi = 10.1016/j.cellsig.2006.12.014 }}
{{refend}}
{{refend}}
{{protein-stub}}
{{WikiDoc Sources}}

Revision as of 18:18, 30 August 2017

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Location (UCSC)n/an/a
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View/Edit Human

DNA-damage-inducible transcript 4 (DDIT4) protein also known as protein regulated in development and DNA damage response 1 (REDD1) is a protein that in humans is encoded by the DDIT4 gene.[1][2]

Function

DDIT4 acts as a negative regulator of mTOR,[3] a serine/threonine kinase that regulates a variety of cellular functions such as growth, proliferation and autophagy.[4] In particular, upregulation of HIF-1 in response to hypoxia upregulates DDIT4,[1] leading to activation of Tsc1/2 via 14–3–3 shuttling [5] and subsequent downregulation of mTOR via Rheb.[6] In addition to hypoxia, DDRT4 expression has also been shown to be activated by DNA damage[7] and energy stress.[8]

In terms of cellular stress, DDIT4 was shown to be induced upon hair follicular damage as a result of loss of the vitamin D receptor. [9] Thus, DDIT4 was shown to regulate both hair growth and wound re-epithelialization interacting via the vitamin D receptor pathway.


Clinical significance

Clinical interest in DDIT4 is based primarily on its effect on mTOR, which has been associated with aging[10] and linked with diseases such as tuberous sclerosis, lymphangioleiomyomatosis,[11] diabetes,[10] and cancer. In particular, the overactivation of mTOR in many cancer types[4] has led to the development of mTOR inhibitors for cancer treatment. DDIT4 has begun to receive attention in this regard via the diabetes drug Metformin which has been shown to reduce cancer risk and increase DDIT4 expression.[12]

See also

References

  1. ↑ 1.0 1.1 Shoshani T, Faerman A, Mett I, Zelin E, Tenne T, Gorodin S, Moshel Y, Elbaz S, Budanov A, Chajut A, Kalinski H, Kamer I, Rozen A, Mor O, Keshet E, Leshkowitz D, Einat P, Skaliter R, Feinstein E (April 2002). "Identification of a novel hypoxia-inducible factor 1-responsive gene, RTP801, involved in apoptosis". Molecular and Cellular Biology. 22 (7): 2283–93. doi:10.1128/MCB.22.7.2283-2293.2002. PMC 133671. PMID 11884613.
  2. ↑ "Entrez Gene: DDIT4 DNA-damage-inducible transcript 4".
  3. ↑ Sofer A, Lei K, Johannessen CM, Ellisen LW (July 2005). "Regulation of mTOR and cell growth in response to energy stress by REDD1". Molecular and Cellular Biology. 25 (14): 5834–45. doi:10.1128/MCB.25.14.5834-5845.2005. PMC 1168803. PMID 15988001.
  4. ↑ 4.0 4.1 Sato T, Nakashima A, Guo L, Coffman K, Tamanoi F (May 2010). "Single amino-acid changes that confer constitutive activation of mTOR are discovered in human cancer". Oncogene. 29 (18): 2746–52. doi:10.1038/onc.2010.28. PMC 2953941. PMID 20190810.
  5. ↑ DeYoung MP, Horak P, Sofer A, Sgroi D, Ellisen LW (January 2008). "Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling". Genes & Development. 22 (2): 239–51. doi:10.1101/gad.1617608. PMC 2192757. PMID 18198340.
  6. ↑ Inoki K, Li Y, Xu T, Guan KL (August 2003). "Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling". Genes & Development. 17 (15): 1829–34. doi:10.1101/gad.1110003. PMC 196227. PMID 12869586.
  7. ↑ Ellisen LW, Ramsayer KD, Johannessen CM, Yang A, Beppu H, Minda K, Oliner JD, McKeon F, Haber DA (November 2002). "REDD1, a developmentally regulated transcriptional target of p63 and p53, links p63 to regulation of reactive oxygen species". Molecular Cell. 10 (5): 995–1005. doi:10.1016/S1097-2765(02)00706-2. PMID 12453409.
  8. ↑ McGhee NK, Jefferson LS, Kimball SR (May 2009). "Elevated corticosterone associated with food deprivation upregulates expression in rat skeletal muscle of the mTORC1 repressor, REDD1". The Journal of Nutrition. 139 (5). doi:10.3945/jn.108.099846. PMC 2714387. PMID 19297425.
  9. ↑ Hengguang Z, Rieger S, Abe K, Hewison M, Lisse T (November 2016). "DNA Damage-Inducible Transcript 4 Is an Innate Surveillant of Hair Follicular Stress in Vitamin D Receptor Knockout Mice and a Regulator of Wound Re-Epithelialization". Int. J. Mol. Sci. 17 (12). doi:10.3390/ijms17121984. PMC 5187784. PMID 27898044.
  10. ↑ 10.0 10.1 Zoncu R, Efeyan A, Sabatini DM (January 2011). "mTOR: from growth signal integration to cancer, diabetes and ageing". Nature Reviews Molecular Cell Biology. 12 (1): 21–35. doi:10.1038/nrm3025. PMC 3390257. PMID 21157483.
  11. ↑ Sarbassov DD, Ali SM, Sabatini DM (December 2005). "Growing roles for the mTOR pathway". Current Opinion in Cell Biology. 17 (6): 596–603. doi:10.1016/j.ceb.2005.09.009. PMID 16226444.
  12. ↑ Ben Sahra I, Regazzetti C, Robert G, Laurent K, Le Marchand-Brustel Y, Auberger P, Tanti JF, Giorgetti-Peraldi S, Bost F (July 2011). "Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1". Cancer Research. 71 (13): 4366–72. doi:10.1158/0008-5472.CAN-10-1769. PMID 21540236.

Further reading

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