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Gene Review

ATF2  -  activating transcription factor 2

Homo sapiens

Synonyms: Activating transcription factor 2, CRE-BP1, CREB-2, CREB2, CREBP1, ...
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Disease relevance of ATF2

  • These findings support other preclinical findings in which transcriptionally active ATF2 is involved in tumor progression-proliferation in melanoma [1].
  • Strong cytoplasmic ATF2 expression was associated with primary specimens rather than metastases (P < 0.0001) and with better survival (P = 0.0003) [1].
  • Activating transcription factor 2 (ATF2) down-regulates hepatitis B virus X promoter activity by the competition for the activating protein 1 binding site and the formation of the ATF2-Jun heterodimer [2].
  • Interleukin-1beta and tetradecanoylphorbol acetate-induced biosynthesis of tumor necrosis factor alpha in human hepatoma cells involves the transcription factors ATF2 and c-Jun and stress-activated protein kinases [3].
  • Sensitization by ATF2 peptide was also observed in the MCF7 human breast cancer cells but not in early-stage melanoma or melanocytes, or in in vitro-transformed 293T cells [4].

Psychiatry related information on ATF2


High impact information on ATF2

  • Using the bZIP domain of ApC/EBP in a two-hybrid system, we have cloned ApCREB2, a transcription factor constitutively expressed in sensory neurons that resembles human CREB2 and mouse ATF4 [7].
  • Second, a GAL4-ATF2 fusion protein can support pRb-mediated transcriptional activation of a promoter containing GAL4-binding sites [8].
  • Retinoblastoma gene product activates expression of the human TGF-beta 2 gene through transcription factor ATF-2 [8].
  • First, the ATF promoter element in the TGF-beta 2 gene is a high-affinity ATF-2-binding site [8].
  • Furthermore, expression of dominant-negative JNK inhibited ATF2 transcriptional activity [9].

Chemical compound and disease context of ATF2


Biological context of ATF2

  • Mutation of the phosphorylation site (Thr196) in CaM-KIV, which mediates its activation by CaM-KIV kinase, prevented activation of Elk-1, c-Jun, and ATF2 by the CaM kinase cascade [14].
  • Enhancement of ATF2-dependent gene expression by p38beta was approximately20-fold greater than that of p38 and other MAP kinases tested [15].
  • Activation of SAPK by forced expression of DeltaMEKK1 increased overall ATF2 ubiquitination, presumably because of the enhanced dimerization of ATF2 [16].
  • However, the small X promoter had a ATF2 binding site and was activated by ATF2 [2].
  • Cotransfection of the ATF2 expression vector with a X promoter-chloramphenicol acetyltransferase plasmid repressed the X promoter activity in HepG2 cells [2].

Anatomical context of ATF2


Associations of ATF2 with chemical compounds

  • The transcription potential of ATF2 is enhanced markedly by NH2-terminal phosphorylation by c-Jun NH2-terminal kinase (JNK) and mediates stress responses including DNA-damaging events [20].
  • Stable expression of ATF2 in human breast carcinoma BT474 cells increases transcriptional activity and confers resistance to the four DNA-damaging agents, but not to transplatin [20].
  • Cycloheximide, which activates SAPK, while inhibiting protein synthesis, stabilized endogenous ATF2 [16].
  • Expression of the cyclic AMP-dependent transcription factors, CREB, CREM and ATF2, in the human myometrium during pregnancy and labour [21].
  • The biological activity of ATF2 is controlled by phosphorylation of two threonine residues within the N-terminal activation domain [22].

Physical interactions of ATF2

  • The phosphorylation/activation of ATF-2 and its binding to PTEN promoter were increased by resistin treatment [23].
  • A second CREB motif closely linked to the S-ATG showed a similar binding pattern involving ATF2 and CREB1, without appearing essential for basal promoter activity [24].
  • TNF acts on the E-selectin gene promoter at three kappa B elements and at a variant cAMP-responsive element that binds ATF2/c-Jun [17].
  • This resulted from the direct protein interaction that the N-terminal transactivation domain of ATF2 interacts with the central region of ASC-2 [18].
  • CREB-2 and ATF-2 bound to CRE serve as an anchor for P300 interaction with upstream transactivators and downstream transcription machinery [25].

Enzymatic interactions of ATF2

  • ATF2 was phosphorylated by JNK on two closely spaced threonine residues within the NH2-terminal activation domain [9].

Regulatory relationships of ATF2


Other interactions of ATF2


Analytical, diagnostic and therapeutic context of ATF2


  1. Subcellular localization of activating transcription factor 2 in melanoma specimens predicts patient survival. Berger, A.J., Kluger, H.M., Li, N., Kielhorn, E., Halaban, R., Ronai, Z., Rimm, D.L. Cancer Res. (2003) [Pubmed]
  2. Activating transcription factor 2 (ATF2) down-regulates hepatitis B virus X promoter activity by the competition for the activating protein 1 binding site and the formation of the ATF2-Jun heterodimer. Choi, C.Y., Choi, B.H., Park, G.T., Rho, H.M. J. Biol. Chem. (1997) [Pubmed]
  3. Interleukin-1beta and tetradecanoylphorbol acetate-induced biosynthesis of tumor necrosis factor alpha in human hepatoma cells involves the transcription factors ATF2 and c-Jun and stress-activated protein kinases. Bauer, I., Al Sarraj, J., Vinson, C., Larsen, R., Thiel, G. J. Cell. Biochem. (2007) [Pubmed]
  4. Activating transcription factor 2-derived peptides alter resistance of human tumor cell lines to ultraviolet irradiation and chemical treatment. Bhoumik, A., Ivanov, V., Ronai, Z. Clin. Cancer Res. (2001) [Pubmed]
  5. Activating transcription factor 2 expression in the adult human brain: association with both neurodegeneration and neurogenesis. Pearson, A.G., Curtis, M.A., Waldvogel, H.J., Faull, R.L., Dragunow, M. Neuroscience (2005) [Pubmed]
  6. Expression of transcription factors c-Fos, c-Jun, CREB-1 and ATF-2, and caspase-3 in relation with abnormal tau deposits in Pick's disease. Nieto-Bodelón, M., Santpere, G., Torrejón-Escribano, B., Puig, B., Ferrer, I. Acta Neuropathol. (2006) [Pubmed]
  7. Aplysia CREB2 represses long-term facilitation: relief of repression converts transient facilitation into long-term functional and structural change. Bartsch, D., Ghirardi, M., Skehel, P.A., Karl, K.A., Herder, S.P., Chen, M., Bailey, C.H., Kandel, E.R. Cell (1995) [Pubmed]
  8. Retinoblastoma gene product activates expression of the human TGF-beta 2 gene through transcription factor ATF-2. Kim, S.J., Wagner, S., Liu, F., O'Reilly, M.A., Robbins, P.D., Green, M.R. Nature (1992) [Pubmed]
  9. Transcription factor ATF2 regulation by the JNK signal transduction pathway. Gupta, S., Campbell, D., Dérijard, B., Davis, R.J. Science (1995) [Pubmed]
  10. Activation of cyclin D1 by estradiol and spermine in MCF-7 breast cancer cells: a mechanism involving the p38 MAP kinase and phosphorylation of ATF-2. Lewis, J.S., Vijayanathan, V., Thomas, T.J., Pestell, R.G., Albanese, C., Gallo, M.A., Thomas, T. Oncol. Res. (2005) [Pubmed]
  11. Contribution of MAP kinase pathways to the activation of ATF-2 in human neuroblastoma cells. Tindberg, N., Porsmyr-Palmertz, M., Simi, A. Neurochem. Res. (2000) [Pubmed]
  12. Ginkgo biloba extract regulates differentially the cell death induced by hydrogen peroxide and simvastatin. Altiok, N., Ersoz, M., Karpuz, V., Koyuturk, M. Neurotoxicology (2006) [Pubmed]
  13. Piperine is a potent inhibitor of nuclear factor-kappaB (NF-kappaB), c-Fos, CREB, ATF-2 and proinflammatory cytokine gene expression in B16F-10 melanoma cells. Pradeep, C.R., Kuttan, G. Int. Immunopharmacol. (2004) [Pubmed]
  14. Regulation of mitogen-activated protein kinases by a calcium/calmodulin-dependent protein kinase cascade. Enslen, H., Tokumitsu, H., Stork, P.J., Davis, R.J., Soderling, T.R. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  15. Characterization of the structure and function of a new mitogen-activated protein kinase (p38beta). Jiang, Y., Chen, C., Li, Z., Guo, W., Gegner, J.A., Lin, S., Han, J. J. Biol. Chem. (1996) [Pubmed]
  16. Stability of the ATF2 transcription factor is regulated by phosphorylation and dephosphorylation. Fuchs, S.Y., Tappin, I., Ronai, Z. J. Biol. Chem. (2000) [Pubmed]
  17. TNF initiates E-selectin transcription in human endothelial cells through parallel TRAF-NF-kappa B and TRAF-RAC/CDC42-JNK-c-Jun/ATF2 pathways. Min, W., Pober, J.S. J. Immunol. (1997) [Pubmed]
  18. Activation and interaction of ATF2 with the coactivator ASC-2 are responsive for granulocytic differentiation by retinoic acid. Hong, S., Choi, H.M., Park, M.J., Kim, Y.H., Choi, Y.H., Kim, H.H., Choi, Y.H., Cheong, J. J. Biol. Chem. (2004) [Pubmed]
  19. Characterization and functional analysis of cAMP response element modulator protein and activating transcription factor 2 (ATF2) isoforms in the human myometrium during pregnancy and labor: identification of a novel ATF2 species with potent transactivation properties. Bailey, J., Phillips, R.J., Pollard, A.J., Gilmore, K., Robson, S.C., Europe-Finner, G.N. J. Clin. Endocrinol. Metab. (2002) [Pubmed]
  20. The activation of c-Jun NH2-terminal kinase (JNK) by DNA-damaging agents serves to promote drug resistance via activating transcription factor 2 (ATF2)-dependent enhanced DNA repair. Hayakawa, J., Depatie, C., Ohmichi, M., Mercola, D. J. Biol. Chem. (2003) [Pubmed]
  21. Expression of the cyclic AMP-dependent transcription factors, CREB, CREM and ATF2, in the human myometrium during pregnancy and labour. Bailey, J., Sparey, C., Phillips, R.J., Gilmore, K., Robson, S.C., Dunlop, W., Europe-Finner, G.N. Mol. Hum. Reprod. (2000) [Pubmed]
  22. Regulation of gene transcription by a constitutively active mutant of activating transcription factor 2 (ATF2). Steinmüller, L., Thiel, G. Biol. Chem. (2003) [Pubmed]
  23. Up-regulation of PTEN (phosphatase and tensin homolog deleted on chromosome ten) mediates p38 MAPK stress signal-induced inhibition of insulin signaling. A cross-talk between stress signaling and insulin signaling in resistin-treated human endothelial cells. Shen, Y.H., Zhang, L., Gan, Y., Wang, X., Wang, J., LeMaire, S.A., Coselli, J.S., Wang, X.L. J. Biol. Chem. (2006) [Pubmed]
  24. CREB/PKA sensitive signalling pathways activate and maintain expression levels of the hepatitis B virus pre-S2/S promoter. Tacke, F., Liedtke, C., Bocklage, S., Manns, M.P., Trautwein, C. Gut (2005) [Pubmed]
  25. Obligatory role of cyclic adenosine monophosphate response element in cyclooxygenase-2 promoter induction and feedback regulation by inflammatory mediators. Schroer, K., Zhu, Y., Saunders, M.A., Deng, W.G., Xu, X.M., Meyer-Kirchrath, J., Wu, K.K. Circulation (2002) [Pubmed]
  26. Spatial and temporal expression of the myometrial mitogen-activated protein kinases p38 and ERK1/2 in the human uterus during pregnancy and labor. Otun, H.A., MacDougall, M.W., Bailey, J., Europe-Finner, G.N., Robson, S.C. J. Soc. Gynecol. Investig. (2005) [Pubmed]
  27. Activating transcription factor-2 regulates phosphoenolpyruvate carboxykinase transcription through a stress-inducible mitogen-activated protein kinase pathway. Cheong, J., Coligan, J.E., Shuman, J.D. J. Biol. Chem. (1998) [Pubmed]
  28. Involvement of the p38 mitogen-activated protein kinase pathway in transforming growth factor-beta-induced gene expression. Hanafusa, H., Ninomiya-Tsuji, J., Masuyama, N., Nishita, M., Fujisawa, J., Shibuya, H., Matsumoto, K., Nishida, E. J. Biol. Chem. (1999) [Pubmed]
  29. House dust mite allergen Der f 2-induced phospholipase D1 activation is critical for the production of interleukin-13 through activating transcription factor-2 activation in human bronchial epithelial cells. Park, S.Y., Cho, J.H., Oh, D.Y., Park, J.W., Ahn, M.J., Han, J.S., Oh, J.W. J. Biol. Chem. (2009) [Pubmed]
  30. Selective interaction of JNK protein kinase isoforms with transcription factors. Gupta, S., Barrett, T., Whitmarsh, A.J., Cavanagh, J., Sluss, H.K., Dérijard, B., Davis, R.J. EMBO J. (1996) [Pubmed]
  31. Biliverdin reductase, a novel regulator for induction of activating transcription factor-2 and heme oxygenase-1. Kravets, A., Hu, Z., Miralem, T., Torno, M.D., Maines, M.D. J. Biol. Chem. (2004) [Pubmed]
  32. Identification of KIN (KIN17), a human gene encoding a nuclear DNA-binding protein, as a novel component of the TP53-independent response to ionizing radiation. Masson, C., Menaa, F., Pinon-Lataillade, G., Frobert, Y., Radicella, J.P., Angulo, J.F. Radiat. Res. (2001) [Pubmed]
  33. The N-terminal transactivation domain of ATF2 is a target for the co-operative activation of the c-jun promoter by p300 and 12S E1A. Duyndam, M.C., van Dam, H., Smits, P.H., Verlaan, M., van der Eb, A.J., Zantema, A. Oncogene (1999) [Pubmed]
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