Activating transcription factor 2

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. 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.{{cite journal | vauthors = Ozawa K, Sudo T, Soeda E, Yoshida MC, Ishii S | title = Assignment of the human CREB2 (CRE-BP1) gene to 2q32 | journal = Genomics | volume = 10 | issue = 4 | pages = 1103–4 | year = 1991 | pmid = 1833307 | doi = 10.1016/0888-7543(91)90210-6 }} 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.{{cite journal | vauthors = Reimold AM, Grusby MJ, Kosaras B, Fries JW, Mori R, Maniwa S, Clauss IM, Collins T, Sidman RL, Glimcher MJ, Glimcher LH | title = Chondrodysplasia and neurological abnormalities in ATF-2-deficient mice | journal = Nature | volume = 379 | issue = 6562 | pages = 262–5 | year = 1996 | pmid = 8538792 | doi = 10.1038/379262a0 | bibcode = 1996Natur.379..262R | s2cid = 4326412 }} ATF-2 is normally activated in response to signals that converge on stress-activated protein kinases p38 and JNK.{{cite journal | vauthors = Gupta S, Campbell D, Dérijard B, Davis RJ | title = Transcription factor ATF2 regulation by the JNK signal transduction pathway | journal = Science | volume = 267 | issue = 5196 | pages = 389–93 | year = 1995 | pmid = 7824938 | doi = 10.1126/science.7824938 | bibcode = 1995Sci...267..389G | s2cid = 40268838 }} ATF-2 phosphorylation in response to treatment of cells with tumor promoter phorbol ester has been demonstrated.{{cite journal | vauthors = Yamasaki T, Takahashi A, Pan J, Yamaguchi N, Yokoyama KK | title = Phosphorylation of Activation Transcription Factor-2 at Serine 121 by Protein Kinase C Controls c-Jun-mediated Activation of Transcription | journal = J. Biol. Chem. | volume = 284 | issue = 13 | pages = 8567–81 | date = March 2009 | pmid = 19176525 | pmc = 2659215 | doi = 10.1074/jbc.M808719200 | doi-access = free }}

Several studies implicate abnormal activation of ATF-2 in growth and progression of mammalian skin tumors.{{cite journal | vauthors = Leslie MC, Bar-Eli M | title = Regulation of gene expression in melanoma: new approaches for treatment | journal = J. Cell. Biochem. | volume = 94 | issue = 1 | pages = 25–38 | year = 2005 | pmid = 15523674 | doi = 10.1002/jcb.20296 | s2cid = 23515325 }}{{cite journal | vauthors = Papassava P, Gorgoulis VG, Papaevangeliou D, Vlahopoulos S, van Dam H, Zoumpourlis V | title = Overexpression of activating transcription factor-2 is required for tumor growth and progression in mouse skin tumors | journal = Cancer Res. | volume = 64 | issue = 23 | pages = 8573–84 | year = 2004 | pmid = 15574764 | doi = 10.1158/0008-5472.CAN-03-0955 | s2cid = 14845890 | doi-access = }} ATF-2 may mediate oncogenesis caused by mutant Ras protein{{cite journal | vauthors = Vlahopoulos SA, Logotheti S, Mikas D, Giarika A, Gorgoulis V, Zoumpourlis V | title = The role of ATF-2 in oncogenesis | journal = BioEssays | volume = 30 | issue = 4 | pages = 314–27 | date = 17 March 2008 | pmid = 18348191 | doi = 10.1002/bies.20734 | s2cid = 678541 }} 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.{{cite journal | vauthors = Bhoumik A, Takahashi S, Breitweiser W, Shiloh Y, Jones N, Ronai Z | title = ATM-dependent phosphorylation of ATF2 is required for the DNA damage response | journal = Mol. Cell | volume = 18 | issue = 5 | pages = 577–87 | date = May 2005 | pmid = 15916964 | pmc = 2954254 | doi = 10.1016/j.molcel.2005.04.015 }} Mice with mutations of these two serines are sensitive to irradiation and easier to tumorigenesis under p53 knockout background.

Activating transcription factor 2 has been shown to interact with

• C-jun,{{cite journal | vauthors = Newell CL, Deisseroth AB, Lopez-Berestein G | title = Interaction of nuclear proteins with an AP-1/CRE-like promoter sequence in the human TNF-alpha gene | journal = J. Leukoc. Biol. | volume = 56 | issue = 1 | pages = 27–35 | date = July 1994 | pmid = 8027667 | doi = 10.1002/jlb.56.1.27| s2cid = 85570533 }}{{cite journal | vauthors = Kara CJ, Liou HC, Ivashkiv LB, Glimcher LH | title = A cDNA for a human cyclic AMP response element-binding protein which is distinct from CREB and expressed preferentially in brain | journal = Mol. Cell. Biol. | volume = 10 | issue = 4 | pages = 1347–57 | date = April 1990 | pmid = 2320002 | pmc = 362236 | doi = 10.1128/MCB.10.4.1347}}{{cite journal | vauthors = Hai T, Curran T | title = Cross-family dimerization of transcription factors Fos/Jun and ATF/CREB alters DNA binding specificity | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 88 | issue = 9 | pages = 3720–4 | date = May 1991 | pmid = 1827203 | pmc = 51524 | doi = 10.1073/pnas.88.9.3720 | bibcode = 1991PNAS...88.3720H | doi-access = free }}
• Casein kinase 2, alpha 1,
• CREB binding protein,{{cite journal | vauthors = Sano Y, Tokitou F, Dai P, Maekawa T, Yamamoto T, Ishii S | title = CBP alleviates the intramolecular inhibition of ATF-2 function | journal = J. Biol. Chem. | volume = 273 | issue = 44 | pages = 29098–105 | date = October 1998 | pmid = 9786917 | doi = 10.1074/jbc.273.44.29098 | doi-access = free }}
• CSNK2A2,{{cite journal | vauthors = Yamaguchi Y, Wada T, Suzuki F, Takagi T, Hasegawa J, Handa H | title = Casein kinase II interacts with the bZIP domains of several transcription factors | journal = Nucleic Acids Res. | volume = 26 | issue = 16 | pages = 3854–61 | date = August 1998 | pmid = 9685505 | pmc = 147779 | doi = 10.1093/nar/26.16.3854 }}
• JDP2,{{cite journal | vauthors = Murata T, Shinozuka Y, Obata Y, Yokoyama KK | title = Phosphorylation of two eukaryotic transcription factors, Jun dimerization protein 2 and activation transcription factor 2, in Escherichia coli by Jun N-terminal kinase 1 | journal = Anal. Biochem. | volume = 376 | issue = 1 | pages = 115–21 | date = May 2008 | pmid = 18307971 | doi = 10.1016/j.ab.2008.01.038 }}
• MAPK14,{{cite journal | vauthors = Raingeaud J, Gupta S, Rogers JS, Dickens M, Han J, Ulevitch RJ, Davis RJ | title = Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine | journal = J. Biol. Chem. | volume = 270 | issue = 13 | pages = 7420–6 | date = March 1995 | pmid = 7535770 | doi = 10.1074/jbc.270.13.7420 | doi-access = free }}{{cite journal | vauthors = Chen Z, Cobb MH | title = Regulation of stress-responsive mitogen-activated protein (MAP) kinase pathways by TAO2 | journal = J. Biol. Chem. | volume = 276 | issue = 19 | pages = 16070–5 | date = May 2001 | pmid = 11279118 | doi = 10.1074/jbc.M100681200 | doi-access = free }}{{cite journal | vauthors = Tournier C, Whitmarsh AJ, Cavanagh J, Barrett T, Davis RJ | title = Mitogen-activated protein kinase kinase 7 is an activator of the c-Jun NH2-terminal kinase | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 94 | issue = 14 | pages = 7337–42 | date = July 1997 | pmid = 9207092 | pmc = 23822 | doi = 10.1073/pnas.94.14.7337 | bibcode = 1997PNAS...94.7337T | doi-access = free }}
• MAPK8,{{cite journal | vauthors = Fuchs SY, Xie B, Adler V, Fried VA, Davis RJ, Ronai Z | title = c-Jun NH2-terminal kinases target the ubiquitination of their associated transcription factors | journal = J. Biol. Chem. | volume = 272 | issue = 51 | pages = 32163–8 | date = December 1997 | pmid = 9405416 | doi = 10.1074/jbc.272.51.32163 | doi-access = free}}
• Mothers against decapentaplegic homolog 3{{cite journal | vauthors = Sano Y, Harada J, Tashiro S, Gotoh-Mandeville R, Maekawa T, Ishii S | title = ATF-2 is a common nuclear target of Smad and TAK1 pathways in transforming growth factor-beta signaling | journal = J. Biol. Chem. | volume = 274 | issue = 13 | pages = 8949–57 | date = March 1999 | pmid = 10085140 | doi = 10.1074/jbc.274.13.8949 | doi-access = free}}
• NCOA6,{{cite journal | vauthors = Hong S, Choi HM, Park MJ, Kim YH, Choi YH, Kim HH, Choi YH, Cheong J | title = Activation and interaction of ATF2 with the coactivator ASC-2 are responsive for granulocytic differentiation by retinoic acid | journal = J. Biol. Chem. | volume = 279 | issue = 17 | pages = 16996–7003 | date = April 2004 | pmid = 14734562 | doi = 10.1074/jbc.M311752200 | doi-access = free }}
• RUVBL2,{{cite journal | vauthors = Cho SG, Bhoumik A, Broday L, Ivanov V, Rosenstein B, Ronai Z | title = TIP49b, a regulator of activating transcription factor 2 response to stress and DNA damage | journal = Mol. Cell. Biol. | volume = 21 | issue = 24 | pages = 8398–413 | date = December 2001 | pmid = 11713276 | pmc = 100004 | doi = 10.1128/MCB.21.24.8398-8413.2001 }}
• UBE2I.{{cite journal | vauthors = Firestein R, Feuerstein N | title = 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 | journal = J. Biol. Chem. | volume = 273 | issue = 10 | pages = 5892–902 | date = March 1998 | pmid = 9488727 | doi = 10.1074/jbc.273.10.5892 | doi-access = free }}

• Activating transcription factor

{{Reflist|35em}}

• {{UCSC gene info|ATF2}}

{{Refbegin|35em}}

• {{cite journal | vauthors = Denys H, Desmet R, Stragier M, Vergison R, Lemahieu SF | title = Cystitis emphysematosa | journal = Acta Urol Belg | volume = 45 | issue = 4 | pages = 327–31 | year = 1977 | pmid = 602896 }}
• {{cite journal | vauthors = Kim SJ, Wagner S, Liu F, O'Reilly MA, Robbins PD, Green MR | title = Retinoblastoma gene product activates expression of the human TGF-beta 2 gene through transcription factor ATF-2 | journal = Nature | volume = 358 | issue = 6384 | pages = 331–4 | year = 1992 | pmid = 1641004 | doi = 10.1038/358331a0 | bibcode = 1992Natur.358..331K | s2cid = 9770957 }}
• {{cite journal | vauthors = Hai T, Curran T | title = Cross-family dimerization of transcription factors Fos/Jun and ATF/CREB alters DNA binding specificity | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 88 | issue = 9 | pages = 3720–4 | year = 1991 | pmid = 1827203 | pmc = 51524 | doi = 10.1073/pnas.88.9.3720 | bibcode = 1991PNAS...88.3720H | doi-access = free }}
• {{cite journal | vauthors = Hoeffler JP, Lustbader JW, Chen CY | title = Identification of multiple nuclear factors that interact with cyclic adenosine 3',5'-monophosphate response element-binding protein and activating transcription factor-2 by protein-protein interactions | journal = Mol. Endocrinol. | volume = 5 | issue = 2 | pages = 256–66 | year = 1991 | pmid = 1828107 | doi = 10.1210/mend-5-2-256 | doi-access = free }}
• {{cite journal | vauthors = Ozawa K, Sudo T, Soeda E, Yoshida MC, Ishii S | title = Assignment of the human CREB2 (CRE-BP1) gene to 2q32 | journal = Genomics | volume = 10 | issue = 4 | pages = 1103–4 | year = 1991 | pmid = 1833307 | doi = 10.1016/0888-7543(91)90210-6 }}
• {{cite journal | vauthors = Diep A, Li C, Klisak I, Mohandas T, Sparkes RS, Gaynor R, Lusis AJ | title = Assignment of the gene for cyclic AMP-response element binding protein 2 (CREB2) to human chromosome 2q24.1-q32 | journal = Genomics | volume = 11 | issue = 4 | pages = 1161–3 | year = 1991 | pmid = 1838349 | doi = 10.1016/0888-7543(91)90047-I }}
• {{cite journal | vauthors = Kara CJ, Liou HC, Ivashkiv LB, Glimcher LH | title = A cDNA for a human cyclic AMP response element-binding protein which is distinct from CREB and expressed preferentially in brain | journal = Mol. Cell. Biol. | volume = 10 | issue = 4 | pages = 1347–57 | year = 1990 | pmid = 2320002 | pmc = 362236 | doi = 10.1128/MCB.10.4.1347}}
• {{cite journal | vauthors = Gonzalez GA, Yamamoto KK, Fischer WH, Karr D, Menzel P, Biggs W, Vale WW, Montminy MR | title = A cluster of phosphorylation sites on the cyclic AMP-regulated nuclear factor CREB predicted by its sequence | journal = Nature | volume = 337 | issue = 6209 | pages = 749–52 | year = 1989 | pmid = 2521922 | doi = 10.1038/337749a0 | bibcode = 1989Natur.337..749G | s2cid = 4345950 }}
• {{cite journal | vauthors = Maekawa T, Sakura H, Kanei-Ishii C, Sudo T, Yoshimura T, Fujisawa J, Yoshida M, Ishii S | title = Leucine zipper structure of the protein CRE-BP1 binding to the cyclic AMP response element in brain | journal = EMBO J. | volume = 8 | issue = 7 | pages = 2023–8 | year = 1989 | pmid = 2529117 | pmc = 401081 | doi = 10.1002/j.1460-2075.1989.tb03610.x}}
• {{cite journal | vauthors = Raingeaud J, Gupta S, Rogers JS, Dickens M, Han J, Ulevitch RJ, Davis RJ | title = Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine | journal = J. Biol. Chem. | volume = 270 | issue = 13 | pages = 7420–6 | year = 1995 | pmid = 7535770 | doi = 10.1074/jbc.270.13.7420 | doi-access = free }}
• {{cite journal | vauthors = Livingstone C, Patel G, Jones N | title = ATF-2 contains a phosphorylation-dependent transcriptional activation domain | journal = EMBO J. | volume = 14 | issue = 8 | pages = 1785–97 | year = 1995 | pmid = 7737129 | pmc = 398272 | doi = 10.1002/j.1460-2075.1995.tb07167.x}}
• {{cite journal | vauthors = van Dam H, Wilhelm D, Herr I, Steffen A, Herrlich P, Angel P | title = ATF-2 is preferentially activated by stress-activated protein kinases to mediate c-jun induction in response to genotoxic agents | journal = EMBO J. | volume = 14 | issue = 8 | pages = 1798–811 | year = 1995 | pmid = 7737130 | pmc = 398273 | doi = 10.1002/j.1460-2075.1995.tb07168.x}}
• {{cite journal | vauthors = Zhou Q, Gedrich RW, Engel DA | title = Transcriptional repression of the c-fos gene by YY1 is mediated by a direct interaction with ATF/CREB | journal = J. Virol. | volume = 69 | issue = 7 | pages = 4323–30 | year = 1995 | pmid = 7769693 | pmc = 189172 | doi = 10.1128/JVI.69.7.4323-4330.1995}}
• {{cite journal | vauthors = Newell CL, Deisseroth AB, Lopez-Berestein G | title = Interaction of nuclear proteins with an AP-1/CRE-like promoter sequence in the human TNF-alpha gene | journal = J. Leukoc. Biol. | volume = 56 | issue = 1 | pages = 27–35 | year = 1994 | pmid = 8027667 | doi = 10.1002/jlb.56.1.27| s2cid = 85570533 }}
• {{cite journal | vauthors = Nomura N, Zu YL, Maekawa T, Tabata S, Akiyama T, Ishii S | title = Isolation and characterization of a novel member of the gene family encoding the cAMP response element-binding protein CRE-BP1 | journal = J. Biol. Chem. | volume = 268 | issue = 6 | pages = 4259–66 | year = 1993 | doi = 10.1016/S0021-9258(18)53604-8 | pmid = 8440710 | doi-access = free }}
• {{cite journal | vauthors = Martin ML, Lieberman PM, Curran T | title = Fos-Jun dimerization promotes interaction of the basic region with TFIIE-34 and TFIIF | journal = Mol. Cell. Biol. | volume = 16 | issue = 5 | pages = 2110–8 | year = 1996 | pmid = 8628277 | pmc = 231198 | doi = 10.1128/mcb.16.5.2110}}
• {{cite journal | vauthors = Yang L, Lanier ER, Kraig E | title = Identification of a novel, spliced variant of CREB that is preferentially expressed in the thymus | journal = J. Immunol. | volume = 158 | issue = 6 | pages = 2522–5 | year = 1997 | doi = 10.4049/jimmunol.158.6.2522 | pmid = 9058782 | s2cid = 29299351 | doi-access = free }}
• {{cite journal | vauthors = Shuman JD, Cheong J, Coligan JE | title = ATF-2 and C/EBPalpha can form a heterodimeric DNA binding complex in vitro. Functional implications for transcriptional regulation | journal = J. Biol. Chem. | volume = 272 | issue = 19 | pages = 12793–800 | year = 1997 | pmid = 9139739 | doi = 10.1074/jbc.272.19.12793 | doi-access = free }}
• {{cite journal | vauthors = Fukunaga R, Hunter T | title = MNK1, a new MAP kinase-activated protein kinase, isolated by a novel expression screening method for identifying protein kinase substrates | journal = EMBO J. | volume = 16 | issue = 8 | pages = 1921–33 | year = 1997 | pmid = 9155018 | pmc = 1169795 | doi = 10.1093/emboj/16.8.1921 }}
• {{cite journal | vauthors = Kumar S, McDonnell PC, Gum RJ, Hand AT, Lee JC, Young PR | title = Novel homologues of CSBP/p38 MAP kinase: activation, substrate specificity and sensitivity to inhibition by pyridinyl imidazoles | journal = Biochem. Biophys. Res. Commun. | volume = 235 | issue = 3 | pages = 533–8 | year = 1997 | pmid = 9207191 | doi = 10.1006/bbrc.1997.6849 }}

{{Refend}}

• [https://www.ebi.ac.uk/pdbe/pdbe-kb/proteins/P15336 PDBe-KB] provides an overview of all the structure information available in the PDB for Human Cyclic AMP-dependent transcription factor ATF-2

{{PDB Gallery|geneid=1386}}

{{Transcription factors|g1}}

{{DEFAULTSORT:Activating Transcription Factor 2}}

Category:Transcription factors

Category:Moonlighting proteins