ATF4

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.[5][6]

ATF4
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1CI6
Identifiers
Aliases	ATF4, CREB-2, CREB2, TAXREB67, TXREB, activating transcription factor 4
External IDs	OMIM: 604064 MGI: 88096 HomoloGene: 1266 GeneCards: ATF4
Gene location (Human) Chr. Chromosome 22 (human)[1] Band 22q13.1 Start 39,519,695 bp[1] End 39,522,685 bp[1]
Gene location (Mouse) Chr. Chromosome 15 (mouse)[2] Band 15 E1|15 37.85 cM Start 80,255,184 bp[2] End 80,257,541 bp[2]
Gene ontology Molecular function • DNA binding • sequence-specific DNA binding • GO:0001131, GO:0001151, GO:0001130, GO:0001204 DNA-binding transcription factor activity • GO:0001077, GO:0001212, GO:0001213, GO:0001211, GO:0001205 DNA-binding transcription activator activity, RNA polymerase II-specific • transcription factor binding • GO:0000980 RNA polymerase II cis-regulatory region sequence-specific DNA binding • core promoter sequence-specific DNA binding • protein C-terminus binding • GO:0001948 protein binding • RNA polymerase II transcription factor binding • leucine zipper domain binding • protein heterodimerization activity • protein kinase binding • GO:0001200, GO:0001133, GO:0001201 DNA-binding transcription factor activity, RNA polymerase II-specific • RNA polymerase II regulatory region sequence-specific DNA binding Cellular component • cytoplasm • ATF1-ATF4 transcription factor complex • ATF4-CREB1 transcription factor complex • transcription regulator complex • dendrite membrane • cell nucleus • Lewy body core • nuclear periphery • membrane • cell membrane • nucleoplasm • microtubule organizing center • neuron projection • cytoskeleton • CHOP-ATF4 complex • centrosome • macromolecular complex • RNA polymerase II transcription factor complex Biological process • gamma-aminobutyric acid signaling pathway • gluconeogenesis • regulation of transcription, DNA-templated • positive regulation of transcription from RNA polymerase II promoter in response to endoplasmic reticulum stress • regulation of transcription from RNA polymerase II promoter • negative regulation of oxidative stress-induced neuron death • cellular response to amino acid starvation • mRNA transcription from RNA polymerase II promoter • circadian regulation of gene expression • response to endoplasmic reticulum stress • PERK-mediated unfolded protein response • response to manganese-induced endoplasmic reticulum stress • positive regulation of transcription, DNA-templated • positive regulation of neuron apoptotic process • intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress • positive regulation of gene expression • positive regulation of transcription from RNA polymerase II promoter in response to oxidative stress • circadian rhythm • negative regulation of potassium ion transport • positive regulation of transcription from RNA polymerase II promoter • positive regulation of transcription from RNA polymerase II promoter in response to arsenic-containing substance • cellular response to glucose starvation • negative regulation of translational initiation in response to stress • rhythmic process • cellular response to UV • positive regulation of transcription from RNA polymerase II promoter in response to stress • cellular amino acid metabolic process • transcription from RNA polymerase II promoter • transcription, DNA-templated • positive regulation of apoptotic process • positive regulation of vascular endothelial growth factor production • positive regulation of transcription from RNA polymerase I promoter • cellular response to dopamine • response to toxic substance • neuron differentiation • cellular response to oxygen-glucose deprivation • positive regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway • cellular calcium ion homeostasis • positive regulation of biomineral tissue development • negative regulation of cold-induced thermogenesis • positive regulation of vascular associated smooth muscle cell apoptotic process • positive regulation of sodium-dependent phosphate transport Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	468	11911
Ensembl	ENSG00000128272	ENSMUSG00000042406
UniProt	P18848	Q06507
RefSeq (mRNA)	NM_182810 NM_001675	NM_001287180 NM_009716
RefSeq (protein)	NP_001666 NP_877962	NP_001274109 NP_033846
Location (UCSC)	Chr 22: 39.52 – 39.52 Mb	Chr 15: 80.26 – 80.26 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

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.[7]

ATF4 transcription factor is also known to play role in osteoblast differentiation along with RUNX2 and osterix.[8] 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.[9] IMPACT protein regulates ATF4 in C. elegans to promote lifespan.[10]

Translation

The translation of ATF4 is dependent on upstream open reading frames located in the 5'UTR.[11] 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.[11]

See also

• Activating transcription factor

References

1. GRCh38: Ensembl release 89: ENSG00000128272 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000042406 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. 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. doi:10.1128/JVI.65.3.1420-1426.1991. PMC 239921. PMID 1847461.
6. 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. Bibcode:1992PNAS...89.4820K. doi:10.1073/pnas.89.11.4820. PMC 49179. PMID 1534408.
7. "Entrez Gene: ATF4 activating transcription factor 4 (tax-responsive enhancer element B67)".
8. 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.
9. 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.
10. 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. PMC 5054600. PMID 27717342.
11. 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. PMC 7172355. PMID 23624144.

Further reading

• Rutkowski DT, Kaufman RJ (April 2003). "All roads lead to ATF4". Developmental Cell. 4 (4): 442–4. doi:10.1016/S1534-5807(03)00100-X. PMID 12689582.
• Nishizawa M, Nagata S (March 1992). "cDNA clones encoding leucine-zipper proteins which interact with G-CSF gene promoter element 1-binding protein". FEBS Letters. 299 (1): 36–8. doi:10.1016/0014-5793(92)80094-W. PMID 1371974. S2CID 34097395.
• 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. Bibcode:1992PNAS...89.4820K. doi:10.1073/pnas.89.11.4820. PMC 49179. PMID 1534408.
• Hai T, Curran T (May 1991). "Cross-family dimerization of transcription factors Fos/Jun and ATF/CREB alters DNA binding specificity". Proceedings of the National Academy of Sciences of the United States of America. 88 (9): 3720–4. Bibcode:1991PNAS...88.3720H. doi:10.1073/pnas.88.9.3720. PMC 51524. PMID 1827203.
• 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. doi:10.1128/JVI.65.3.1420-1426.1991. PMC 239921. PMID 1847461.
• Hai TW, Liu F, Coukos WJ, Green MR (December 1989). "Transcription factor ATF cDNA clones: an extensive family of leucine zipper proteins able to selectively form DNA-binding heterodimers". Genes & Development. 3 (12B): 2083–90. doi:10.1101/gad.3.12b.2083. PMID 2516827.
• Kokame K, Kato H, Miyata T (November 1996). "Homocysteine-respondent genes in vascular endothelial cells identified by differential display analysis. GRP78/BiP and novel genes". The Journal of Biological Chemistry. 271 (47): 29659–65. doi:10.1074/jbc.271.47.29659. PMID 8939898.
• Reddy TR, Tang H, Li X, Wong-Staal F (June 1997). "Functional interaction of the HTLV-1 transactivator Tax with activating transcription factor-4 (ATF4)". Oncogene. 14 (23): 2785–92. doi:10.1038/sj.onc.1201119. PMID 9190894.
• Liang G, Hai T (September 1997). "Characterization of human activating transcription factor 4, a transcriptional activator that interacts with multiple domains of cAMP-responsive element-binding protein (CREB)-binding protein". The Journal of Biological Chemistry. 272 (38): 24088–95. doi:10.1074/jbc.272.38.24088. PMID 9295363.
• Kawai T, Matsumoto M, Takeda K, Sanjo H, Akira S (March 1998). "ZIP kinase, a novel serine/threonine kinase which mediates apoptosis". Molecular and Cellular Biology. 18 (3): 1642–51. doi:10.1128/mcb.18.3.1642. PMC 108879. PMID 9488481.
• Outinen PA, Sood SK, Pfeifer SI, Pamidi S, Podor TJ, Li J, Weitz JI, Austin RC (August 1999). "Homocysteine-induced endoplasmic reticulum stress and growth arrest leads to specific changes in gene expression in human vascular endothelial cells". Blood. 94 (3): 959–67. doi:10.1182/blood.V94.3.959.415k20_959_967. PMID 10419887.
• Podust LM, Krezel AM, Kim Y (January 2001). "Crystal structure of the CCAAT box/enhancer-binding protein beta activating transcription factor-4 basic leucine zipper heterodimer in the absence of DNA". The Journal of Biological Chemistry. 276 (1): 505–13. doi:10.1074/jbc.M005594200. PMID 11018027.
• Murphy P, Kolstø A (October 2000). "Expression of the bZIP transcription factor TCF11 and its potential dimerization partners during development". Mechanisms of Development. 97 (1–2): 141–8. doi:10.1016/S0925-4773(00)00413-5. PMID 11025215. S2CID 17474070.
• White JH, McIllhinney RA, Wise A, Ciruela F, Chan WY, Emson PC, Billinton A, Marshall FH (December 2000). "The GABAB receptor interacts directly with the related transcription factors CREB2 and ATFx". Proceedings of the National Academy of Sciences of the United States of America. 97 (25): 13967–72. Bibcode:2000PNAS...9713967W. doi:10.1073/pnas.240452197. PMC 17684. PMID 11087824.
• He CH, Gong P, Hu B, Stewart D, Choi ME, Choi AM, Alam J (June 2001). "Identification of activating transcription factor 4 (ATF4) as an Nrf2-interacting protein. Implication for heme oxygenase-1 gene regulation". The Journal of Biological Chemistry. 276 (24): 20858–65. doi:10.1074/jbc.M101198200. PMID 11274184.
• Siu F, Bain PJ, LeBlanc-Chaffin R, Chen H, Kilberg MS (July 2002). "ATF4 is a mediator of the nutrient-sensing response pathway that activates the human asparagine synthetase gene". The Journal of Biological Chemistry. 277 (27): 24120–7. doi:10.1074/jbc.M201959200. PMID 11960987.
• Bowers AJ, Scully S, Boylan JF (May 2003). "SKIP3, a novel Drosophila tribbles ortholog, is overexpressed in human tumors and is regulated by hypoxia". Oncogene. 22 (18): 2823–35. doi:10.1038/sj.onc.1206367. PMID 12743605.
• Seo J, Fortuno ES, Suh JM, Stenesen D, Tang W, Parks EJ, Adams CM, Townes T, Graff JM (November 2009). "Atf4 regulates obesity, glucose homeostasis, and energy expenditure". Diabetes. 58 (11): 2565–73. doi:10.2337/db09-0335. PMC 2768187. PMID 19690063.
• Ebert, S. M., Bullard, S. A., Basisty, N., Marcotte, G. R., Skopec, Z. P., Dierdorff, J. M., ... & Bodine, S. C. (2020). "Activating transcription factor 4 (ATF4) promotes skeletal muscle atrophy by forming a heterodimer with the transcriptional regulator C/EBPβ". Journal of Biological Chemistry, 295(9), 2787–2803. doi:10.1074/jbc.RA119.012095 PMC 7049960 PMID 31953319

External links

• ATF4+protein,+human at the US National Library of Medicine Medical Subject Headings (MeSH)
• Human ATF4 genome location and ATF4 gene details page in the UCSC Genome Browser.
• PDBe-KB provides an overview of all the structure information available in the PDB for Human Cyclic AMP-dependent transcription factor ATF-4

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