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Gene Review

Atf2  -  activating transcription factor 2

Mus musculus

Synonyms: ATF-2, Activating transcription factor 2, Atf-2, CRE-BP, Creb2, ...
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Disease relevance of Atf2

  • ATF-2 mutant mice proved more susceptible to death than control mice from LPS plus D-galactosamine injection or Coxsackievirus B3 infection and had a higher incidence of mononuclear pulmonary infiltrates after exposure to Herpes simplex virus-1 [1].
  • The notorious resistance of melanoma cells to drug treatment can be overcome by expression of a 50-aa peptide derived from activating transcription factor 2 (ATF2(50-100)) [2].
  • In immunocytochemical and immunoblotting experiments we have shown that simvastatin markedly increased the phosphorylation of ATF-2 and c-jun in the nucleus of the C6 glioma cells at early time points which was preserved even 24 h after treatment [3].
  • An ATF2-derived peptide sensitizes melanomas to apoptosis and inhibits their growth and metastasis [4].
  • Heterodimer formation of cJun and ATF-2 is responsible for induction of c-jun by the 243 amino acid adenovirus E1A protein [5].

High impact information on Atf2


Biological context of Atf2


Anatomical context of Atf2

  • In a previous report, we showed a progressive increase in the levels of various activator protein (AP)-1 components, including phosphorylated ATF-2, in a series of mouse skin cell lines that represented developmental stages of the mouse skin carcinogenesis system [13].
  • P38 and activating transcription factor-2 involvement in osteoblast osmotic response to elevated extracellular glucose [14].
  • Stimulation of T lymphocytes by anti-CD3 antibody also showed less induction of IL-1 and IL-6 in ATF-2 mutant tissues [1].
  • The multisite phosphorylation of the transcription factor ATF-2 was investigated using transformed embryonic fibroblasts from wild-type mice and mice deficient in c-Jun N-terminal kinases (JNK)1 and 2, and in the presence and absence of inhibitors of p38 mitogen-activated protein kinase (p38 MAPK) and the classical MAP kinase cascade [15].
  • Jun N-terminal kinase (JNK), a known phosphorylator of c-Jun and ATF-2, increased in activity in LPS-stimulated monocytes [16].

Associations of Atf2 with chemical compounds


Physical interactions of Atf2


Enzymatic interactions of Atf2


Regulatory relationships of Atf2


Other interactions of Atf2

  • Therefore, we propose that hyperglycemia-induced increases in p38 MAPK activity and ATF-2 phosphorylation contribute to CRE activation and modulation of c-jun and collagen I expression in osteoblasts [14].
  • We have isolated cDNA clones, TCR-ATF1 and TCR-ATF2, encoding DNA-binding proteins that recognize this CRE motif [28].
  • Subsequently, we observed that dominant negative ATF-2 affected the composition and reduced the activity of AP-1 [13].
  • ATF-2 mutant thymocytes treated with anti-CD3 antibody in vitro demonstrated reduced induction of c-Jun, JunB, JunD and Fra-2 [1].
  • p38/RK is essential for stress-induced nuclear responses: JNK/SAPKs and c-Jun/ATF-2 phosphorylation are insufficient [29].

Analytical, diagnostic and therapeutic context of Atf2

  • Immunoprecipitation and glutaraldehyde cross-linking studies show that mXBP/CRE-BP2 can form a complex with c-Jun [30].
  • Mouse null mutants of transcription factor ATF-2 were generated by the gene targeting method [31].
  • Electrophoretic mobility-shift assays demonstrated that NF-kappaB binding activity induced by IL-1beta or LPS was also increased in K-rasAsp12-transfected cells, along with the binding of CREB-1, CREM-1, ATF-1, ATF-2, and Jun D to a cAMP-responsive element (CRE)-like site and the binding of C/EBPbeta to a C/EBP-binding consensus site [32].
  • The assay involves immobilization of the respective kinase substrates c-Jun, Elk1, or ATF2 on microtiter plates, addition of the kinase reaction mixture, and measurement of substrate phosphorylation using phospho-epitope-specific antibodies [33].
  • The p38 mitogen-activated protein kinase activation and kinase activity were determined by Western blotting with monoclonal antibodies for the phosphorylated from of p38 mitogen-activated protein kinase or its substrate, activating transcription factor 2 [34].


  1. Decreased immediate inflammatory gene induction in activating transcription factor-2 mutant mice. Reimold, A.M., Kim, J., Finberg, R., Glimcher, L.H. Int. Immunol. (2001) [Pubmed]
  2. Transcriptional switch by activating transcription factor 2-derived peptide sensitizes melanoma cells to apoptosis and inhibits their tumorigenicity. Bhoumik, A., Jones, N., Ronai, Z. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  3. Simvastatin induces proliferation inhibition and apoptosis in C6 glioma cells via c-jun N-terminal kinase. Koyuturk, M., Ersoz, M., Altiok, N. Neurosci. Lett. (2004) [Pubmed]
  4. An ATF2-derived peptide sensitizes melanomas to apoptosis and inhibits their growth and metastasis. Bhoumik, A., Huang, T.G., Ivanov, V., Gangi, L., Qiao, R.F., Woo, S.L., Chen, S.H., Ronai, Z. J. Clin. Invest. (2002) [Pubmed]
  5. Heterodimer formation of cJun and ATF-2 is responsible for induction of c-jun by the 243 amino acid adenovirus E1A protein. van Dam, H., Duyndam, M., Rottier, R., Bosch, A., de Vries-Smits, L., Herrlich, P., Zantema, A., Angel, P., van der Eb, A.J. EMBO J. (1993) [Pubmed]
  6. Chondrodysplasia and neurological abnormalities in ATF-2-deficient mice. Reimold, A.M., Grusby, M.J., Kosaras, B., Fries, J.W., Mori, R., Maniwa, S., Clauss, I.M., Collins, T., Sidman, R.L., Glimcher, M.J., Glimcher, L.H. Nature (1996) [Pubmed]
  7. Distinct cloned class II MHC DNA binding proteins recognize the X box transcription element. Liou, H.C., Boothby, M.R., Glimcher, L.H. Science (1988) [Pubmed]
  8. p300 and ATF-2 are components of the DRF complex, which regulates retinoic acid- and E1A-mediated transcription of the c-jun gene in F9 cells. Kawasaki, H., Song, J., Eckner, R., Ugai, H., Chiu, R., Taira, K., Shi, Y., Jones, N., Yokoyama, K.K. Genes Dev. (1998) [Pubmed]
  9. p38MAPK acts in the BMP7-dependent stimulatory pathway during epithelial cell morphogenesis and is regulated by Smad1. Hu, M.C., Wasserman, D., Hartwig, S., Rosenblum, N.D. J. Biol. Chem. (2004) [Pubmed]
  10. pp60(v-src) induction of cyclin D1 requires collaborative interactions between the extracellular signal-regulated kinase, p38, and Jun kinase pathways. A role for cAMP response element-binding protein and activating transcription factor-2 in pp60(v-src) signaling in breast cancer cells. Lee, R.J., Albanese, C., Stenger, R.J., Watanabe, G., Inghirami, G., Haines, G.K., Webster, M., Muller, W.J., Brugge, J.S., Davis, R.J., Pestell, R.G. J. Biol. Chem. (1999) [Pubmed]
  11. Cdc42Hs, but not Rac1, inhibits serum-stimulated cell cycle progression at G1/S through a mechanism requiring p38/RK. Molnár, A., Theodoras, A.M., Zon, L.I., Kyriakis, J.M. J. Biol. Chem. (1997) [Pubmed]
  12. Hepatocyte growth factor/scatter factor activates proliferation in melanoma cells through p38 MAPK, ATF-2 and cyclin D1. Recio, J.A., Merlino, G. Oncogene (2002) [Pubmed]
  13. Overexpression of activating transcription factor-2 is required for tumor growth and progression in mouse skin tumors. Papassava, P., Gorgoulis, V.G., Papaevangeliou, D., Vlahopoulos, S., van Dam, H., Zoumpourlis, V. Cancer Res. (2004) [Pubmed]
  14. P38 and activating transcription factor-2 involvement in osteoblast osmotic response to elevated extracellular glucose. Zayzafoon, M., Botolin, S., McCabe, L.R. J. Biol. Chem. (2002) [Pubmed]
  15. Signalling pathways involved in multisite phosphorylation of the transcription factor ATF-2. Morton, S., Davis, R.J., Cohen, P. FEBS Lett. (2004) [Pubmed]
  16. A distinct element involved in lipopolysaccharide activation of the tumor necrosis factor-alpha promoter in monocytes. Diaz, B., Lopez-Berestein, G. J. Interferon Cytokine Res. (2000) [Pubmed]
  17. Ceramide activates the stress-activated protein kinases. Westwick, J.K., Bielawska, A.E., Dbaibo, G., Hannun, Y.A., Brenner, D.A. J. Biol. Chem. (1995) [Pubmed]
  18. Multiple basic-leucine zipper proteins regulate induction of the mouse heme oxygenase-1 gene by arsenite. Gong, P., Stewart, D., Hu, B., Vinson, C., Alam, J. Arch. Biochem. Biophys. (2002) [Pubmed]
  19. The high mobility group protein HMG I(Y) can stimulate or inhibit DNA binding of distinct transcription factor ATF-2 isoforms. Du, W., Maniatis, T. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  20. Induction of E-selectin expression by double-stranded RNA and TNF-alpha is attenuated in murine aortic endothelial cells derived from double-stranded RNA-activated kinase (PKR)-null mice. Bandyopadhyay, S.K., de La Motte, C.A., Williams, B.R. J. Immunol. (2000) [Pubmed]
  21. CNS myelinogenesis in vitro: myelin basic protein deficient shiverer oligodendrocytes. Seiwa, C., Kojima-Aikawa, K., Matsumoto, I., Asou, H. J. Neurosci. Res. (2002) [Pubmed]
  22. Transcriptional activation of the small GTPase gene rhoB by genotoxic stress is regulated via a CCAAT element. Fritz, G., Kaina, B. Nucleic Acids Res. (2001) [Pubmed]
  23. ATF-2-binding regulatory element is responsible for the Ly49A expression in murine T lymphoid line, EL-4. Kubo, S., Nagasawa, R., Nishimura, H., Shigemoto, K., Maruyama, N. Biochim. Biophys. Acta (1999) [Pubmed]
  24. Regulation of activating transcription factor-2 in early stage of the adipocyte differentiation program. Lee, M.Y., Kong, H.J., Cheong, J. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  25. p38 Mitogen-activated protein kinase regulation of JB6 Cl41 cell transformation promoted by epidermal growth factor. He, Z., Cho, Y.Y., Liu, G., Ma, W.Y., Bode, A.M., Dong, Z. J. Biol. Chem. (2003) [Pubmed]
  26. 17beta-estradiol activation of the c-Jun N-terminal kinase pathway leads to down-regulation of class II major histocompatibility complex expression. Adamski, J., Benveniste, E.N. Mol. Endocrinol. (2005) [Pubmed]
  27. Identification of the cyclin D1 gene as a target of activating transcription factor 2 in chondrocytes. Beier, F., Lee, R.J., Taylor, A.C., Pestell, R.G., LuValle, P. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  28. Isolation and characterization of nuclear proteins that bind to T cell receptor V beta decamer motif. Lee, M.R., Chung, C.S., Liou, M.L., Wu, M., Li, W.F., Hsueh, Y.P., Lai, M.Z. J. Immunol. (1992) [Pubmed]
  29. p38/RK is essential for stress-induced nuclear responses: JNK/SAPKs and c-Jun/ATF-2 phosphorylation are insufficient. Hazzalin, C.A., Cano, E., Cuenda, A., Barratt, M.J., Cohen, P., Mahadevan, L.C. Curr. Biol. (1996) [Pubmed]
  30. mXBP/CRE-BP2 and c-Jun form a complex which binds to the cyclic AMP, but not to the 12-O-tetradecanoylphorbol-13-acetate, response element. Ivashkiv, L.B., Liou, H.C., Kara, C.J., Lamph, W.W., Verma, I.M., Glimcher, L.H. Mol. Cell. Biol. (1990) [Pubmed]
  31. Mouse ATF-2 null mutants display features of a severe type of meconium aspiration syndrome. Maekawa, T., Bernier, F., Sato, M., Nomura, S., Singh, M., Inoue, Y., Tokunaga, T., Imai, H., Yokoyama, M., Reimold, A., Glimcher, L.H., Ishii, S. J. Biol. Chem. (1999) [Pubmed]
  32. Transfection of K-rasAsp12 cDNA markedly elevates IL-1beta- and lipopolysaccharide-mediated inducible nitric oxide synthase expression in rat intestinal epithelial cells. Takahashi, M., Mutoh, M., Shoji, Y., Kamanaka, Y., Naka, M., Maruyama, T., Sugimura, T., Wakabayashi, K. Oncogene (2003) [Pubmed]
  33. Enzyme-linked immunosorbent assay for measurement of JNK, ERK, and p38 kinase activities. Forrer, P., Tamaskovic, R., Jaussi, R. Biol. Chem. (1998) [Pubmed]
  34. FR167653 diminishes infarct size in a murine model of myocardial ischemia-reperfusion injury. Yada, M., Shimamoto, A., Hampton, C.R., Chong, A.J., Takayama, H., Rothnie, C.L., Spring, D.J., Shimpo, H., Yada, I., Pohlman, T.H., Verrier, E.D. J. Thorac. Cardiovasc. Surg. (2004) [Pubmed]
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