This gene encodes a transcription factor that is a member of the leucine zipper family of DNA-binding proteins. This protein binds to the cAMP-responsive element (CRE), an octameric palindrome. The protein forms a homodimer or heterodimer with c-Jun and stimulates CRE-dependent transcription. The protein is also a histone acetyltransferase (HAT) that specifically acetylates histones H2B and H4 in vitro; thus, it may represent a class of sequence-specific factors that activate transcription by direct effects on chromatin components. Additional transcript variants have been identified but their biological validity has not been determined.
The gene atf2 is located at human chromosome 2q32. The protein ATF-2 has 505 amino acids. Studies in mice indicate a role for ATF-2 in the development of nervous system and the skeleton. ATF-2 is normally activated in response to signals that converge on stress-activated protein kinases p38 and JNK. ATF-2 phosphorylation in response to treatment of cells with tumor promoter phorbol ester has been demonstrated.
Several studies implicate abnormal activation of ATF-2 in growth and progression of mammalian skin tumors. ATF-2 may mediate oncogenesis caused by mutant Ras protein and regulate maintenance of the aggressive cancer phenotype of some types of epithelial cells. ATF2 has also been shown to be phosphorylated at its C-terminal (Serine 472 and 480 in mouse; Serine 490 and 498 in human) by ATM upon double-stranded breaks. Mice with mutations of these two serines are sensitive to irradiation and easier to tumorigenesis under p53 knockout background.
^Leslie MC, Bar-Eli M (2005). "Regulation of gene expression in melanoma: new approaches for treatment". J. Cell. Biochem.94 (1): 25–38. doi:10.1002/jcb.20296. PMID15523674.
^Papassava P, Gorgoulis VG, Papaevangeliou D, Vlahopoulos S, van Dam H, Zoumpourlis V (2004). "Overexpression of activating transcription factor-2 is required for tumor growth and progression in mouse skin tumors". Cancer Res.64 (23): 8573–84. doi:10.1158/0008-5472.CAN-03-0955. PMID15574764.
^Vlahopoulos SA, Logotheti S, Mikas D, Giarika A, Gorgoulis V, Zoumpourlis V (17 March 2008). "The role of ATF-2 in oncogenesis". Bioessays30 (4): 314–27. doi:10.1002/bies.20734. PMID18348191.CS1 maint: Date and year (link)
^Newell CL, Deisseroth AB, Lopez-Berestein G (July 1994). "Interaction of nuclear proteins with an AP-1/CRE-like promoter sequence in the human TNF-alpha gene". J. Leukoc. Biol.56 (1): 27–35. PMID8027667.CS1 maint: Date and year (link)
^Sano Y, Tokitou F, Dai P, Maekawa T, Yamamoto T, Ishii S (October 1998). "CBP alleviates the intramolecular inhibition of ATF-2 function". J. Biol. Chem.273 (44): 29098–105. doi:10.1074/jbc.273.44.29098. PMID9786917.CS1 maint: Date and year (link)
^Murata T, Shinozuka Y, Obata Y, Yokoyama KK (May 2008). "Phosphorylation of two eukaryotic transcription factors, Jun dimerization protein 2 and activation transcription factor 2, in Escherichia coli by Jun N-terminal kinase 1". Anal. Biochem.376 (1): 115–21. doi:10.1016/j.ab.2008.01.038. PMID18307971.CS1 maint: Date and year (link)
^ abRaingeaud J, Gupta S, Rogers JS, Dickens M, Han J, Ulevitch RJ et al. (March 1995). "Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine". J. Biol. Chem.270 (13): 7420–6. doi:10.1074/jbc.270.13.7420. PMID7535770.CS1 maint: Date and year (link)
^ abChen Z, Cobb MH (May 2001). "Regulation of stress-responsive mitogen-activated protein (MAP) kinase pathways by TAO2". J. Biol. Chem.276 (19): 16070–5. doi:10.1074/jbc.M100681200. PMID11279118.CS1 maint: Date and year (link)
^Fuchs SY, Xie B, Adler V, Fried VA, Davis RJ, Ronai Z (December 1997). "c-Jun NH2-terminal kinases target the ubiquitination of their associated transcription factors". J. Biol. Chem.272 (51): 32163–8. doi:10.1074/jbc.272.51.32163. PMID9405416.CS1 maint: Date and year (link)
^Sano Y, Harada J, Tashiro S, Gotoh-Mandeville R, Maekawa T, Ishii S (March 1999). "ATF-2 is a common nuclear target of Smad and TAK1 pathways in transforming growth factor-beta signaling". J. Biol. Chem.274 (13): 8949–57. doi:10.1074/jbc.274.13.8949. PMID10085140.CS1 maint: Date and year (link)
^Hong S, Choi HM, Park MJ, Kim YH, Choi YH, Kim HH et al. (April 2004). "Activation and interaction of ATF2 with the coactivator ASC-2 are responsive for granulocytic differentiation by retinoic acid". J. Biol. Chem.279 (17): 16996–7003. doi:10.1074/jbc.M311752200. PMID14734562.CS1 maint: Date and year (link)
^Firestein R, Feuerstein N (March 1998). "Association of activating transcription factor 2 (ATF2) with the ubiquitin-conjugating enzyme hUBC9. Implication of the ubiquitin/proteasome pathway in regulation of ATF2 in T cells". J. Biol. Chem.273 (10): 5892–902. doi:10.1074/jbc.273.10.5892. PMID9488727.CS1 maint: Date and year (link)
Denys H, Desmet R, Stragier M, Vergison R, Lemahieu SF (1977). "Cystitis emphysematosa". Acta Urol Belg45 (4): 327–31. PMID602896.
Kim SJ, Wagner S, Liu F, O'Reilly MA, Robbins PD, Green MR (1992). "Retinoblastoma gene product activates expression of the human TGF-beta 2 gene through transcription factor ATF-2". Nature358 (6384): 331–4. doi:10.1038/358331a0. PMID1641004.
Diep A, Li C, Klisak I, Mohandas T, Sparkes RS, Gaynor R et al. (1991). "Assignment of the gene for cyclic AMP-response element binding protein 2 (CREB2) to human chromosome 2q24.1-q32". Genomics11 (4): 1161–3. doi:10.1016/0888-7543(91)90047-I. PMID1838349.
Gonzalez GA, Yamamoto KK, Fischer WH, Karr D, Menzel P, Biggs W et al. (1989). "A cluster of phosphorylation sites on the cyclic AMP-regulated nuclear factor CREB predicted by its sequence". Nature337 (6209): 749–52. doi:10.1038/337749a0. PMID2521922.
Raingeaud J, Gupta S, Rogers JS, Dickens M, Han J, Ulevitch RJ et al. (1995). "Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine". J. Biol. Chem.270 (13): 7420–6. doi:10.1074/jbc.270.13.7420. PMID7535770.
Newell CL, Deisseroth AB, Lopez-Berestein G (1994). "Interaction of nuclear proteins with an AP-1/CRE-like promoter sequence in the human TNF-alpha gene". J. Leukoc. Biol.56 (1): 27–35. PMID8027667.
Nomura N, Zu YL, Maekawa T, Tabata S, Akiyama T, Ishii S (1993). "Isolation and characterization of a novel member of the gene family encoding the cAMP response element-binding protein CRE-BP1". J. Biol. Chem.268 (6): 4259–66. PMID8440710.
Yang L, Lanier ER, Kraig E (1997). "Identification of a novel, spliced variant of CREB that is preferentially expressed in the thymus". J. Immunol.158 (6): 2522–5. PMID9058782.
Shuman JD, Cheong J, Coligan JE (1997). "ATF-2 and C/EBPalpha can form a heterodimeric DNA binding complex in vitro. Functional implications for transcriptional regulation". J. Biol. Chem.272 (19): 12793–800. doi:10.1074/jbc.272.19.12793. PMID9139739.