Activating transcription factor 4 (tax-responsive enhancer element B67), also known asATF4, is aprotein that in humans is encoded by theATF4gene.[5][6]
This gene encodes atranscription 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 theAP-1 family of transcription factors, cAMP-response element binding proteins (CREBs) and CREB-like proteins. These transcription factors share aleucine zipper region that is involved in protein–protein interactions, locatedC-terminal to a stretch of basic amino acids that functions as aDNA-binding domain. Two alternative transcripts encoding the same protein have been described. Twopseudogenes 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 inosteoblast differentiation along withRUNX2 andosterix.[8] Terminal osteoblast differentiation, represented by matrix mineralization, is significantly inhibited by the inactivation ofJNK. JNK inactivation downregulates expression of ATF-4 and, subsequently, matrix mineralization.[9] IMPACT protein regulates ATF4 in C. elegans to promote lifespan.[10]
The translation of ATF4 is dependent onupstream open reading frames located in the5'UTR.[13] The location of the second uORF, aptly named uORF2, overlaps with theATF4 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 theATF4 ORF, whose start codon is located within uORF2. This leads to its repression. However, during stress conditions, the40S 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. InsteadATF4 is translated.[13]
^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.S2CID13111270.
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):2785–2792.doi:10.1038/sj.onc.1201119.PMID9190894.S2CID3199765.
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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):141–148.doi:10.1016/S0925-4773(00)00413-5.PMID11025215.S2CID17474070.
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):2823–2835.doi:10.1038/sj.onc.1206367.PMID12743605.S2CID22769991.
