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<!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. -->
{{Infobox_gene}}
{{PBB_Controls
'''Activating transcription factor 4 (tax-responsive enhancer element B67)''', also known as '''ATF4''', is a [[protein]] that in humans is encoded by the ''ATF4''  [[gene]].<ref name="pmid1847461">{{cite journal | vauthors = Tsujimoto A, Nyunoya H, Morita T, Sato T, Shimotohno K | title = Isolation of cDNAs for DNA-binding proteins which specifically bind to a tax-responsive enhancer element in the long terminal repeat of human T-cell leukemia virus type I | journal = Journal of Virology | volume = 65 | issue = 3 | pages = 1420–6 | date = March 1991 | pmid = 1847461 | pmc = 239921 | doi =  | url = http://jvi.asm.org/cgi/content/abstract/65/3/1420 }}</ref><ref name="pmid1534408">{{cite journal | vauthors = Karpinski BA, Morle GD, Huggenvik J, Uhler MD, Leiden JM | title = Molecular cloning of human CREB-2: an ATF/CREB transcription factor that can negatively regulate transcription from the cAMP response element | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 89 | issue = 11 | pages = 4820–4 | date = June 1992 | pmid = 1534408 | pmc = 49179 | doi = 10.1073/pnas.89.11.4820 }}</ref>
| update_page = yes
 
| require_manual_inspection = no
== Function ==
| update_protein_box = yes
 
| update_summary = yes
This gene encodes a [[transcription factor]] that was originally identified as a widely expressed mammalian DNA binding protein that could bind a tax-responsive enhancer element in the LTR of HTLV-1. The encoded protein was also isolated and characterized as the cAMP-response element binding protein 2 ([[activating transcription factor 2|CREB-2]]). The protein encoded by this gene belongs to a family of DNA-binding proteins that includes the [[AP-1 (transcription factor)|AP-1]] family of transcription factors, cAMP-response element binding proteins ([[CREB]]s) and CREB-like proteins. These transcription factors share a [[leucine zipper]] region that is involved in protein–protein interactions, located [[C-terminus|C-terminal]] to a stretch of basic amino acids that functions as a [[DNA-binding domain]]. Two alternative transcripts encoding the same protein have been described. Two [[pseudogene]]s are located on the X chromosome at q28 in a region containing a large inverted duplication.<ref name="entrez">{{cite web | title = Entrez Gene: ATF4 activating transcription factor 4 (tax-responsive enhancer element B67)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=468| access-date = }}</ref>
| update_citations = yes
 
}}
ATF4 transcription factor is also known to play role in [[osteoblast]] differentiation along with [[RUNX2]] and [[Sp7 transcription factor|osterix]].<ref name="pmid18728356">{{cite journal | vauthors = Franceschi RT, Ge C, Xiao G, Roca H, Jiang D | title = Transcriptional regulation of osteoblasts | journal = Cells Tissues Organs | volume = 189 | issue = 1-4 | pages = 144–52 | year = 2009 | pmid = 18728356 | pmc = 3512205 | doi = 10.1159/000151747 }}</ref> Terminal osteoblast differentiation, represented by matrix mineralization, is significantly inhibited by the inactivation of [[c-Jun N-terminal kinases|JNK]]. JNK inactivation downregulates expression of ATF-4 and, subsequently, matrix mineralization.<ref name="pmid19016586">{{cite journal | vauthors = Matsuguchi T, Chiba N, Bandow K, Kakimoto K, Masuda A, Ohnishi T | title = JNK activity is essential for Atf4 expression and late-stage osteoblast differentiation | journal = Journal of Bone and Mineral Research | volume = 24 | issue = 3 | pages = 398–410 | date = March 2009 | pmid = 19016586 | doi = 10.1359/jbmr.081107 }}</ref> IMPACT protein regulates ATF4 in C. elegans to promote lifespan.<ref>{{cite journal | vauthors = Ferraz RC, Camara H, De-Souza EA, Pinto S, Pinca AP, Silva RC, Sato VN, Castilho BA, Mori MA | title = IMPACT is a GCN2 inhibitor that limits lifespan in Caenorhabditis elegans | journal = BMC Biology | volume = 14 | issue = 1 | pages = 87 | date = October 2016 | pmid = 27717342 | doi = 10.1186/s12915-016-0301-2 | url = https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-016-0301-2 }}</ref>


<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Translation ==
{{GNF_Protein_box
| image = PBB_Protein_ATF4_image.jpg
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 1ci6.
| PDB = {{PDB2|1ci6}}
| Name = Activating transcription factor 4 (tax-responsive enhancer element B67)
| HGNCid = 786
| Symbol = ATF4
| AltSymbols =; CREB-2; CREB2; TAXREB67; TXREB
| OMIM = 604064
| ECnumber = 
| Homologene = 1266
| MGIid = 88096
| Function = {{GNF_GO|id=GO:0003700 |text = transcription factor activity}} {{GNF_GO|id=GO:0003704 |text = specific RNA polymerase II transcription factor activity}} {{GNF_GO|id=GO:0016563 |text = transcription activator activity}} {{GNF_GO|id=GO:0043565 |text = sequence-specific DNA binding}} {{GNF_GO|id=GO:0046983 |text = protein dimerization activity}}
| Component = {{GNF_GO|id=GO:0005634 |text = nucleus}} {{GNF_GO|id=GO:0005737 |text = cytoplasm}}
| Process = {{GNF_GO|id=GO:0006094 |text = gluconeogenesis}} {{GNF_GO|id=GO:0006350 |text = transcription}} {{GNF_GO|id=GO:0006355 |text = regulation of transcription, DNA-dependent}} {{GNF_GO|id=GO:0006520 |text = amino acid metabolic process}} {{GNF_GO|id=GO:0006950 |text = response to stress}} {{GNF_GO|id=GO:0045944 |text = positive regulation of transcription from RNA polymerase II promoter}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 468
    | Hs_Ensembl = 
    | Hs_RefseqProtein = NP_001666
    | Hs_RefseqmRNA = NM_001675
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 
    | Hs_GenLoc_start = 
    | Hs_GenLoc_end = 
    | Hs_Uniprot = 
    | Mm_EntrezGene = 11911
    | Mm_Ensembl = ENSMUSG00000042406
    | Mm_RefseqmRNA = NM_009716
    | Mm_RefseqProtein = NP_033846
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 15
    | Mm_GenLoc_start = 80082439
    | Mm_GenLoc_end = 80084794
    | Mm_Uniprot = Q3U2J1
  }}
}}
'''Activating transcription factor 4 (tax-responsive enhancer element B67)''', also known as '''ATF4''', is a human [[gene]].


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot. See Template:PBB_Controls to Stop updates. -->
The translation of ATF4 is dependent on [[upstream open reading frame]]s located in the [[5'UTR]].<ref name="Somers_2013">{{cite journal | vauthors = Somers J, Pöyry T, Willis AE | title = A perspective on mammalian upstream open reading frame function | journal = The International Journal of Biochemistry & Cell Biology | volume = 45 | issue = 8 | pages = 1690–700 | date = August 2013 | pmid = 23624144 | doi = 10.1016/j.biocel.2013.04.020 }}</ref>  The location of the second uORF, aptly named uORF2, overlaps with the ''ATF4'' open-reading frame. During normal conditions, the uORF1 is translated, and then translation of uORF2 occurs only after eIF2-TC has been reacquired. Translation of the uORF2 requires that the ribosomes pass by the ''ATF4'' ORF, whose start codon is located within uORF2. This leads to its repression.  However, during stress conditions, the [[40S]] ribosome will bypass uORF2 because of a decrease in concentration of eIF2-TC, which means the ribosome does not acquire one in time to translate uORF2. Instead ''ATF4'' is translated.<ref name="Somers_2013"/>
{{PBB_Summary
| section_title =  
| summary_text = This gene encodes a transcription factor that was originally identified as a widely expressed mammalian DNA binding protein that could bind a tax-responsive enhancer element in the LTR of HTLV-1. The encoded protein was also isolated and characterized as the cAMP-response element binding protein 2 (CREB-2). The protein encoded by this gene belongs to a family of DNA-binding proteins that includes the AP-1 family of transcription factors, cAMP-response element binding proteins (CREBs) and CREB-like proteins. These transcription factors share a leucine zipper region that is involved in protein-protein interactions, located C-terminal to a stretch of basic amino acids that functions as a DNA binding domain. Two alternative transcripts encoding the same protein have been described. Two pseudogenes are located on the X chromsome at q28 in a region containing a large inverted duplication.<ref name="entrez">{{cite web | title = Entrez Gene: ATF4 activating transcription factor 4 (tax-responsive enhancer element B67)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=468| accessdate = }}</ref>
}}


==See also==
== See also ==
* [[Activating transcription factor]]
* [[Activating transcription factor]]


==References==
== References ==
{{reflist|2}}
{{reflist}}


==Further reading==
== Further reading ==
{{refbegin | 2}}
{{refbegin | 2}}
{{PBB_Further_reading
* {{cite journal | vauthors = Rutkowski DT, Kaufman RJ | title = All roads lead to ATF4 | journal = Developmental Cell | volume = 4 | issue = 4 | pages = 442–4 | date = April 2003 | pmid = 12689582 | doi = 10.1016/S1534-5807(03)00100-X }}
| citations =
* {{cite journal | vauthors = Nishizawa M, Nagata S | title = cDNA clones encoding leucine-zipper proteins which interact with G-CSF gene promoter element 1-binding protein | journal = FEBS Letters | volume = 299 | issue = 1 | pages = 36–8 | date = March 1992 | pmid = 1371974 | doi = 10.1016/0014-5793(92)80094-W }}
*{{cite journal | author=Rutkowski DT, Kaufman RJ |title=All roads lead to ATF4. |journal=Dev. Cell |volume=4 |issue= 4 |pages= 442-4 |year= 2003 |pmid= 12689582 |doi= }}
* {{cite journal | vauthors = Karpinski BA, Morle GD, Huggenvik J, Uhler MD, Leiden JM | title = Molecular cloning of human CREB-2: an ATF/CREB transcription factor that can negatively regulate transcription from the cAMP response element | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 89 | issue = 11 | pages = 4820–4 | date = June 1992 | pmid = 1534408 | pmc = 49179 | doi = 10.1073/pnas.89.11.4820 }}
*{{cite journal | author=Nishizawa M, Nagata S |title=cDNA clones encoding leucine-zipper proteins which interact with G-CSF gene promoter element 1-binding protein. |journal=FEBS Lett. |volume=299 |issue= 1 |pages= 36-8 |year= 1992 |pmid= 1371974 |doi= }}
* {{cite journal | vauthors = Hai T, Curran T | title = Cross-family dimerization of transcription factors Fos/Jun and ATF/CREB alters DNA binding specificity | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 88 | issue = 9 | pages = 3720–4 | date = May 1991 | pmid = 1827203 | pmc = 51524 | doi = 10.1073/pnas.88.9.3720 }}
*{{cite journal | author=Karpinski BA, Morle GD, Huggenvik J, ''et al.'' |title=Molecular cloning of human CREB-2: an ATF/CREB transcription factor that can negatively regulate transcription from the cAMP response element. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=89 |issue= 11 |pages= 4820-4 |year= 1992 |pmid= 1534408 |doi= }}
* {{cite journal | vauthors = Tsujimoto A, Nyunoya H, Morita T, Sato T, Shimotohno K | title = Isolation of cDNAs for DNA-binding proteins which specifically bind to a tax-responsive enhancer element in the long terminal repeat of human T-cell leukemia virus type I | journal = Journal of Virology | volume = 65 | issue = 3 | pages = 1420–6 | date = March 1991 | pmid = 1847461 | pmc = 239921 | doi =  }}
*{{cite journal | author=Hai T, Curran T |title=Cross-family dimerization of transcription factors Fos/Jun and ATF/CREB alters DNA binding specificity. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=88 |issue= 9 |pages= 3720-4 |year= 1991 |pmid= 1827203 |doi= }}
* {{cite journal | vauthors = Hai TW, Liu F, Coukos WJ, Green MR | title = Transcription factor ATF cDNA clones: an extensive family of leucine zipper proteins able to selectively form DNA-binding heterodimers | journal = Genes & Development | volume = 3 | issue = 12B | pages = 2083–90 | date = December 1989 | pmid = 2516827 | doi = 10.1101/gad.3.12b.2083 }}
*{{cite journal | author=Tsujimoto A, Nyunoya H, Morita T, ''et al.'' |title=Isolation of cDNAs for DNA-binding proteins which specifically bind to a tax-responsive enhancer element in the long terminal repeat of human T-cell leukemia virus type I. |journal=J. Virol. |volume=65 |issue= 3 |pages= 1420-6 |year= 1991 |pmid= 1847461 |doi=  }}
* {{cite journal | vauthors = Kokame K, Kato H, Miyata T | title = Homocysteine-respondent genes in vascular endothelial cells identified by differential display analysis. GRP78/BiP and novel genes | journal = The Journal of Biological Chemistry | volume = 271 | issue = 47 | pages = 29659–65 | date = November 1996 | pmid = 8939898 | doi = 10.1074/jbc.271.47.29659 }}
*{{cite journal | author=Hai TW, Liu F, Coukos WJ, Green MR |title=Transcription factor ATF cDNA clones: an extensive family of leucine zipper proteins able to selectively form DNA-binding heterodimers. |journal=Genes Dev. |volume=3 |issue= 12B |pages= 2083-90 |year= 1990 |pmid= 2516827 |doi= }}
* {{cite journal | vauthors = Reddy TR, Tang H, Li X, Wong-Staal F | title = Functional interaction of the HTLV-1 transactivator Tax with activating transcription factor-4 (ATF4) | journal = Oncogene | volume = 14 | issue = 23 | pages = 2785–92 | date = June 1997 | pmid = 9190894 | doi = 10.1038/sj.onc.1201119 }}
*{{cite journal | author=Kokame K, Kato H, Miyata T |title=Homocysteine-respondent genes in vascular endothelial cells identified by differential display analysis. GRP78/BiP and novel genes. |journal=J. Biol. Chem. |volume=271 |issue= 47 |pages= 29659-65 |year= 1997 |pmid= 8939898 |doi= }}
* {{cite journal | vauthors = Liang G, Hai T | title = Characterization of human activating transcription factor 4, a transcriptional activator that interacts with multiple domains of cAMP-responsive element-binding protein (CREB)-binding protein | journal = The Journal of Biological Chemistry | volume = 272 | issue = 38 | pages = 24088–95 | date = September 1997 | pmid = 9295363 | doi = 10.1074/jbc.272.38.24088 }}
*{{cite journal | author=Reddy TR, Tang H, Li X, Wong-Staal F |title=Functional interaction of the HTLV-1 transactivator Tax with activating transcription factor-4 (ATF4). |journal=Oncogene |volume=14 |issue= 23 |pages= 2785-92 |year= 1997 |pmid= 9190894 |doi= 10.1038/sj.onc.1201119 }}
* {{cite journal | vauthors = Kawai T, Matsumoto M, Takeda K, Sanjo H, Akira S | title = ZIP kinase, a novel serine/threonine kinase which mediates apoptosis | journal = Molecular and Cellular Biology | volume = 18 | issue = 3 | pages = 1642–51 | date = March 1998 | pmid = 9488481 | pmc = 108879 | doi = 10.1128/mcb.18.3.1642 }}
*{{cite journal | author=Liang G, Hai T |title=Characterization of human activating transcription factor 4, a transcriptional activator that interacts with multiple domains of cAMP-responsive element-binding protein (CREB)-binding protein. |journal=J. Biol. Chem. |volume=272 |issue= 38 |pages= 24088-95 |year= 1997 |pmid= 9295363 |doi= }}
* {{cite journal | vauthors = Outinen PA, Sood SK, Pfeifer SI, Pamidi S, Podor TJ, Li J, Weitz JI, Austin RC | title = Homocysteine-induced endoplasmic reticulum stress and growth arrest leads to specific changes in gene expression in human vascular endothelial cells | journal = Blood | volume = 94 | issue = 3 | pages = 959–67 | date = August 1999 | pmid = 10419887 | doi =  }}
*{{cite journal | author=Kawai T, Matsumoto M, Takeda K, ''et al.'' |title=ZIP kinase, a novel serine/threonine kinase which mediates apoptosis. |journal=Mol. Cell. Biol. |volume=18 |issue= 3 |pages= 1642-51 |year= 1998 |pmid= 9488481 |doi= }}
* {{cite journal | vauthors = Podust LM, Krezel AM, Kim Y | title = Crystal structure of the CCAAT box/enhancer-binding protein beta activating transcription factor-4 basic leucine zipper heterodimer in the absence of DNA | journal = The Journal of Biological Chemistry | volume = 276 | issue = 1 | pages = 505–13 | date = January 2001 | pmid = 11018027 | doi = 10.1074/jbc.M005594200 }}
*{{cite journal | author=Outinen PA, Sood SK, Pfeifer SI, ''et al.'' |title=Homocysteine-induced endoplasmic reticulum stress and growth arrest leads to specific changes in gene expression in human vascular endothelial cells. |journal=Blood |volume=94 |issue= 3 |pages= 959-67 |year= 1999 |pmid= 10419887 |doi=  }}
* {{cite journal | vauthors = Murphy P, Kolstø A | title = Expression of the bZIP transcription factor TCF11 and its potential dimerization partners during development | journal = Mechanisms of Development | volume = 97 | issue = 1-2 | pages = 141–8 | date = October 2000 | pmid = 11025215 | doi = 10.1016/S0925-4773(00)00413-5 }}
*{{cite journal | author=Dunham I, Shimizu N, Roe BA, ''et al.'' |title=The DNA sequence of human chromosome 22. |journal=Nature |volume=402 |issue= 6761 |pages= 489-95 |year= 1999 |pmid= 10591208 |doi= 10.1038/990031 }}
* {{cite journal | vauthors = White JH, McIllhinney RA, Wise A, Ciruela F, Chan WY, Emson PC, Billinton A, Marshall FH | title = The GABAB receptor interacts directly with the related transcription factors CREB2 and ATFx | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 25 | pages = 13967–72 | date = December 2000 | pmid = 11087824 | pmc = 17684 | doi = 10.1073/pnas.240452197 }}
*{{cite journal  | author=Podust LM, Krezel AM, Kim Y |title=Crystal structure of the CCAAT box/enhancer-binding protein beta activating transcription factor-4 basic leucine zipper heterodimer in the absence of DNA. |journal=J. Biol. Chem. |volume=276 |issue= 1 |pages= 505-13 |year= 2001 |pmid= 11018027 |doi= 10.1074/jbc.M005594200 }}
* {{cite journal | vauthors = He CH, Gong P, Hu B, Stewart D, Choi ME, Choi AM, Alam J | title = Identification of activating transcription factor 4 (ATF4) as an Nrf2-interacting protein. Implication for heme oxygenase-1 gene regulation | journal = The Journal of Biological Chemistry | volume = 276 | issue = 24 | pages = 20858–65 | date = June 2001 | pmid = 11274184 | doi = 10.1074/jbc.M101198200 }}
*{{cite journal | author=Murphy P, Kolstø A |title=Expression of the bZIP transcription factor TCF11 and its potential dimerization partners during development. |journal=Mech. Dev. |volume=97 |issue= 1-2 |pages= 141-8 |year= 2001 |pmid= 11025215 |doi= }}
* {{cite journal | vauthors = Siu F, Bain PJ, LeBlanc-Chaffin R, Chen H, Kilberg MS | title = ATF4 is a mediator of the nutrient-sensing response pathway that activates the human asparagine synthetase gene | journal = The Journal of Biological Chemistry | volume = 277 | issue = 27 | pages = 24120–7 | date = July 2002 | pmid = 11960987 | doi = 10.1074/jbc.M201959200 }}
*{{cite journal | author=White JH, McIllhinney RA, Wise A, ''et al.'' |title=The GABAB receptor interacts directly with the related transcription factors CREB2 and ATFx. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=97 |issue= 25 |pages= 13967-72 |year= 2001 |pmid= 11087824 |doi= 10.1073/pnas.240452197 }}
* {{cite journal | vauthors = Bowers AJ, Scully S, Boylan JF | title = SKIP3, a novel Drosophila tribbles ortholog, is overexpressed in human tumors and is regulated by hypoxia | journal = Oncogene | volume = 22 | issue = 18 | pages = 2823–35 | date = May 2003 | pmid = 12743605 | doi = 10.1038/sj.onc.1206367 }}
*{{cite journal | author=He CH, Gong P, Hu B, ''et al.'' |title=Identification of activating transcription factor 4 (ATF4) as an Nrf2-interacting protein. Implication for heme oxygenase-1 gene regulation. |journal=J. Biol. Chem. |volume=276 |issue= 24 |pages= 20858-65 |year= 2001 |pmid= 11274184 |doi= 10.1074/jbc.M101198200 }}
* {{cite journal | vauthors = Seo J, Fortuno ES, Suh JM, Stenesen D, Tang W, Parks EJ, Adams CM, Townes T, Graff JM | title = Atf4 regulates obesity, glucose homeostasis, and energy expenditure | journal = Diabetes | volume = 58 | issue = 11 | pages = 2565–73 | date = November 2009 | pmid = 19690063 | pmc = 2768187 | doi = 10.2337/db09-0335 }}
*{{cite journal | author=Siu F, Bain PJ, LeBlanc-Chaffin R, ''et al.'' |title=ATF4 is a mediator of the nutrient-sensing response pathway that activates the human asparagine synthetase gene. |journal=J. Biol. Chem. |volume=277 |issue= 27 |pages= 24120-7 |year= 2002 |pmid= 11960987 |doi= 10.1074/jbc.M201959200 }}
*{{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 | author=Bowers AJ, Scully S, Boylan JF |title=SKIP3, a novel Drosophila tribbles ortholog, is overexpressed in human tumors and is regulated by hypoxia. |journal=Oncogene |volume=22 |issue= 18 |pages= 2823-35 |year= 2003 |pmid= 12743605 |doi= 10.1038/sj.onc.1206367 }}
}}
{{refend}}
{{refend}}


== External links ==
== External links ==
* {{MeshName|ATF4+protein,+human}}
* {{MeshName|ATF4+protein,+human}}
* {{UCSC gene info|ATF4}}


{{NLM content}}
{{NLM content}}
{{protein-stub}}
 
{{Transcription factors}}
{{PDB Gallery|geneid=468}}
{{Transcription factors|g1}}
{{Regulome
| activates = Runx2, nrf1,Bip
| inhibits = ATF4, CHOP
| activated_by = not, PERK
| inhibited_by =
}}
 
[[Category:Transcription factors]]
[[Category:Transcription factors]]
{{WikiDoc Sources}}

Latest revision as of 12:25, 9 January 2019

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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
PubMed searchn/an/a
Wikidata
View/Edit Human

Activating transcription factor 4 (tax-responsive enhancer element B67), also known as ATF4, is a protein that in humans is encoded by the ATF4 gene.[1][2]

Function

This gene encodes a transcription factor that was originally identified as a widely expressed mammalian DNA binding protein that could bind a tax-responsive enhancer element in the LTR of HTLV-1. The encoded protein was also isolated and characterized as the cAMP-response element binding protein 2 (CREB-2). The protein encoded by this gene belongs to a family of DNA-binding proteins that includes the AP-1 family of transcription factors, cAMP-response element binding proteins (CREBs) and CREB-like proteins. These transcription factors share a leucine zipper region that is involved in protein–protein interactions, located C-terminal to a stretch of basic amino acids that functions as a DNA-binding domain. Two alternative transcripts encoding the same protein have been described. Two pseudogenes are located on the X chromosome at q28 in a region containing a large inverted duplication.[3]

ATF4 transcription factor is also known to play role in osteoblast differentiation along with RUNX2 and osterix.[4] Terminal osteoblast differentiation, represented by matrix mineralization, is significantly inhibited by the inactivation of JNK. JNK inactivation downregulates expression of ATF-4 and, subsequently, matrix mineralization.[5] IMPACT protein regulates ATF4 in C. elegans to promote lifespan.[6]

Translation

The translation of ATF4 is dependent on upstream open reading frames located in the 5'UTR.[7] The location of the second uORF, aptly named uORF2, overlaps with the ATF4 open-reading frame. During normal conditions, the uORF1 is translated, and then translation of uORF2 occurs only after eIF2-TC has been reacquired. Translation of the uORF2 requires that the ribosomes pass by the ATF4 ORF, whose start codon is located within uORF2. This leads to its repression. However, during stress conditions, the 40S ribosome will bypass uORF2 because of a decrease in concentration of eIF2-TC, which means the ribosome does not acquire one in time to translate uORF2. Instead ATF4 is translated.[7]

See also

References

  1. ↑ Tsujimoto A, Nyunoya H, Morita T, Sato T, Shimotohno K (March 1991). "Isolation of cDNAs for DNA-binding proteins which specifically bind to a tax-responsive enhancer element in the long terminal repeat of human T-cell leukemia virus type I". Journal of Virology. 65 (3): 1420–6. PMC 239921. PMID 1847461.
  2. ↑ Karpinski BA, Morle GD, Huggenvik J, Uhler MD, Leiden JM (June 1992). "Molecular cloning of human CREB-2: an ATF/CREB transcription factor that can negatively regulate transcription from the cAMP response element". Proceedings of the National Academy of Sciences of the United States of America. 89 (11): 4820–4. doi:10.1073/pnas.89.11.4820. PMC 49179. PMID 1534408.
  3. ↑ "Entrez Gene: ATF4 activating transcription factor 4 (tax-responsive enhancer element B67)".
  4. ↑ Franceschi RT, Ge C, Xiao G, Roca H, Jiang D (2009). "Transcriptional regulation of osteoblasts". Cells Tissues Organs. 189 (1–4): 144–52. doi:10.1159/000151747. PMC 3512205. PMID 18728356.
  5. ↑ Matsuguchi T, Chiba N, Bandow K, Kakimoto K, Masuda A, Ohnishi T (March 2009). "JNK activity is essential for Atf4 expression and late-stage osteoblast differentiation". Journal of Bone and Mineral Research. 24 (3): 398–410. doi:10.1359/jbmr.081107. PMID 19016586.
  6. ↑ Ferraz RC, Camara H, De-Souza EA, Pinto S, Pinca AP, Silva RC, Sato VN, Castilho BA, Mori MA (October 2016). "IMPACT is a GCN2 inhibitor that limits lifespan in Caenorhabditis elegans". BMC Biology. 14 (1): 87. doi:10.1186/s12915-016-0301-2. PMID 27717342.
  7. ↑ 7.0 7.1 Somers J, Pöyry T, Willis AE (August 2013). "A perspective on mammalian upstream open reading frame function". The International Journal of Biochemistry & Cell Biology. 45 (8): 1690–700. doi:10.1016/j.biocel.2013.04.020. PMID 23624144.

Further reading

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.


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