ATF4

Activating transcription factor 4
PDB rendering based on 1ci6.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1CI6​
Identifiers
Symbols	ATF4 ; CREB-2; CREB2; TAXREB67; TXREB
External IDs	OMIM: 604064 MGI: 88096 HomoloGene: 1266 GeneCards: ATF4 Gene
Gene ontology Molecular function • RNA polymerase II core promoter proximal region sequence-specific DNA binding • RNA polymerase II transcription factor activity, sequence-specific DNA binding • core promoter sequence-specific DNA binding • transcription factor activity, RNA polymerase II transcription factor binding • transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding • RNA polymerase II transcription factor binding • DNA binding • transcription factor activity, sequence-specific DNA binding • protein binding • protein C-terminus binding • leucine zipper domain binding • sequence-specific DNA binding • transcription regulatory region DNA binding • protein heterodimerization activity Cellular component • nucleus • nucleoplasm • cytoplasm • microtubule organizing center • dendrite membrane • nuclear periphery • neuron projection • Lewy body core • ATF4-CREB1 transcription factor complex • ATF1-ATF4 transcription factor complex • CHOP-ATF4 complex Biological process • gluconeogenesis • regulation of transcription, DNA-templated • transcription from RNA polymerase II promoter • cellular amino acid metabolic process • gamma-aminobutyric acid signaling pathway • positive regulation of vascular endothelial growth factor production • positive regulation of gene expression • endoplasmic reticulum unfolded protein response • circadian regulation of gene expression • cellular response to amino acid starvation • response to endoplasmic reticulum stress • positive regulation of transcription from RNA polymerase II promoter in response to oxidative stress • PERK-mediated unfolded protein response • cellular response to glucose starvation • positive regulation of apoptotic process • negative regulation of potassium ion transport • positive regulation of neuron apoptotic process • cellular protein metabolic process • positive regulation of transcription, DNA-templated • positive regulation of transcription from RNA polymerase I promoter • positive regulation of transcription from RNA polymerase II promoter • positive regulation of transcription from RNA polymerase II promoter in response to arsenic-containing substance • intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress • negative regulation of oxidative stress-induced neuron death • positive regulation of transcription from RNA polymerase II promoter in response to endoplasmic reticulum stress Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	468	11911
Ensembl	ENSG00000128272	ENSMUSG00000042406
UniProt	P18848	Q06507
RefSeq (mRNA)	NM_001675	NM_001287180
RefSeq (protein)	NP_001666	NP_001274109
Location (UCSC)	Chr 22: 39.52 – 39.52 Mb	Chr 15: 80.26 – 80.26 Mb
PubMed search

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]

Translation

The translation of ATF4 is dependent on upstream open reading frames located in the 5'UTR.^[6] 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.^[6]

Interactions

Kir2.1 has been shown to interact with:

• DLG4,^[7]
• IL16,^[8] and
• TRAK2.^[9]

See also

• Activating transcription factor

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 : the Official Journal of the American Society for Bone and Mineral Research 24 (3): 398–410. doi:10.1359/jbmr.081107. PMID 19016586.
6. Somers J, Pöyry T, Willis AE (August 2013). "A perspective on mammalian upstream open reading frame function". Int. J. Biochem. Cell Biol. 45 (8): 1690–700. doi:10.1016/j.biocel.2013.04.020. PMID 23624144.
7. Nehring RB, Wischmeyer E, Döring F, Veh RW, Sheng M, Karschin A (2000). "Neuronal inwardly rectifying K(+) channels differentially couple to PDZ proteins of the PSD-95/SAP90 family". J. Neurosci. 20 (1): 156–62. PMID 10627592.
8. Kurschner C, Yuzaki M (1999). "Neuronal interleukin-16 (NIL-16): a dual function PDZ domain protein". J. Neurosci. 19 (18): 7770–80. PMID 10479680.
9. Grishin A, Li H, Levitan ES, Zaks-Makhina E (2006). "Identification of gamma-aminobutyric acid receptor-interacting factor 1 (TRAK2) as a trafficking factor for the K+ channel Kir2.1". J. Biol. Chem. 281 (40): 30104–11. doi:10.1074/jbc.M602439200. PMID 16895905.

Further reading

• Rutkowski DT, Kaufman RJ (2003). "All roads lead to ATF4". Dev. Cell 4 (4): 442–4. doi:10.1016/S1534-5807(03)00100-X. PMID 12689582.
• Nishizawa M, Nagata S (1992). "cDNA clones encoding leucine-zipper proteins which interact with G-CSF gene promoter element 1-binding protein". FEBS Lett. 299 (1): 36–8. doi:10.1016/0014-5793(92)80094-W. PMID 1371974.
• Karpinski BA, Morle GD, Huggenvik J, Uhler MD, Leiden JM (1992). "Molecular cloning of human CREB-2: an ATF/CREB transcription factor that can negatively regulate transcription from the cAMP response element". Proc. Natl. Acad. Sci. U.S.A. 89 (11): 4820–4. doi:10.1073/pnas.89.11.4820. PMC 49179. PMID 1534408.
• Hai T, Curran T (1991). "Cross-family dimerization of transcription factors Fos/Jun and ATF/CREB alters DNA binding specificity". Proc. Natl. Acad. Sci. U.S.A. 88 (9): 3720–4. doi:10.1073/pnas.88.9.3720. PMC 51524. PMID 1827203.
• Tsujimoto A, Nyunoya H, Morita T, Sato T, Shimotohno K (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". J. Virol. 65 (3): 1420–6. PMC 239921. PMID 1847461.
• Hai TW, Liu F, Coukos WJ, Green MR (1990). "Transcription factor ATF cDNA clones: an extensive family of leucine zipper proteins able to selectively form DNA-binding heterodimers". Genes Dev. 3 (12B): 2083–90. doi:10.1101/gad.3.12b.2083. PMID 2516827.
• Kokame K, Kato H, Miyata T (1997). "Homocysteine-respondent genes in vascular endothelial cells identified by differential display analysis. GRP78/BiP and novel genes". J. Biol. Chem. 271 (47): 29659–65. doi:10.1074/jbc.271.47.29659. PMID 8939898.
• Reddy TR, Tang H, Li X, Wong-Staal F (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 (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". J. Biol. Chem. 272 (38): 24088–95. doi:10.1074/jbc.272.38.24088. PMID 9295363.
• Kawai T, Matsumoto M, Takeda K, Sanjo H, Akira S (1998). "ZIP Kinase, a Novel Serine/Threonine Kinase Which Mediates Apoptosis". Mol. Cell. Biol. 18 (3): 1642–51. PMC 108879. PMID 9488481.
• Outinen PA, Sood SK, Pfeifer SI, Pamidi S, Podor TJ, Li J, Weitz JI, Austin RC (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. PMID 10419887.
• Podust LM, Krezel AM, Kim Y (2001). "Crystal structure of the CCAAT box/enhancer-binding protein beta activating transcription factor-4 basic leucine zipper heterodimer in the absence of DNA". J. Biol. Chem. 276 (1): 505–13. doi:10.1074/jbc.M005594200. PMID 11018027.
• Murphy P, Kolstø A (2001). "Expression of the bZIP transcription factor TCF11 and its potential dimerization partners during development". Mech. Dev. 97 (1–2): 141–8. doi:10.1016/S0925-4773(00)00413-5. PMID 11025215.
• White JH, McIllhinney RA, Wise A, Ciruela F, Chan WY, Emson PC, Billinton A, Marshall FH (2001). "The GABAB receptor interacts directly with the related transcription factors CREB2 and ATFx". Proc. Natl. Acad. Sci. U.S.A. 97 (25): 13967–72. doi:10.1073/pnas.240452197. PMC 17684. PMID 11087824.
• He CH, Gong P, Hu B, Stewart D, Choi ME, Choi AM, Alam J (2001). "Identification of activating transcription factor 4 (ATF4) as an Nrf2-interacting protein. Implication for heme oxygenase-1 gene regulation". J. Biol. Chem. 276 (24): 20858–65. doi:10.1074/jbc.M101198200. PMID 11274184.
• Siu F, Bain PJ, LeBlanc-Chaffin R, Chen H, Kilberg MS (2002). "ATF4 is a mediator of the nutrient-sensing response pathway that activates the human asparagine synthetase gene". J. Biol. Chem. 277 (27): 24120–7. doi:10.1074/jbc.M201959200. PMID 11960987.
• Bowers AJ, Scully S, Boylan JF (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 (2009). "Atf4 Regulates Obesity, Glucose Homeostasis, and Energy Expenditure". Diabetes 58 (11): 2565–2573. doi:10.2337/db09-0335. PMC 2768187. PMID 19690063.

External links

• ATF4 protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)

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