Activating transcription factor 4 (tax-responsive enhancer element B67), also known as ATF4, is a protein that in humans is encoded by the ATF4gene.[1][2]
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]
↑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. PMID19016586.
↑ 6.06.1Somers 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. PMID23624144.
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. PMID1371974.
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. PMID2516827.
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. PMID8939898.
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. PMID9190894.
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. PMID9295363.
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. PMID10419887.
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. PMID11018027.
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. PMID11025215.
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. PMID11274184.
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. PMID11960987.
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. PMID12743605.