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ATF-2 controls transcription of Maspin and GADD45α genes independently from p53 to suppress mammary tumors

A Corrigendum to this article was published on 03 July 2014

Abstract

The activating transcription factor, ATF-2, is a target of p38 and JNK that are involved in stress-induced apoptosis. Heterozygous Atf-2 mutant (Atf-2+/−) mice are highly prone to mammary tumors. The apoptosis-regulated gene GADD45α and the breast cancer suppressor gene Maspin, both of which are known to be p53 target genes, are downregulated in the mammary tumors arisen in Atf-2+/− mice. Here, we have analysed how ATF-2 controls the transcription of GADD45α and Maspin. ATF-2 and p53 independently activate the GADD45α transcription. ATF-2 does not directly bind to the GADD45α promoter; instead, it is recruited via Oct-1 and NF-I. ATF-2 simultaneously binds to Oct-1, NF-I and breast cancer suppressor BRCA1 to activate transcription. With regard to Maspin, ATF-2 and p53 directly bind to different sites in the Maspin promoter to independently activate its transcription. Consistent with the observation that ATF-2 and p53 independently activate the transcription of Maspin and GADD45α is that the loss of one copy of p53 shortened the period required for mammary tumor development in Atf-2+/− mice. These studies suggest the functional link between the ATF-2 and the two tumor suppressors BRCA1 and p53.

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References

  • Chang L, Karin M . (2001). Mammalian MAP kinase signalling cascades. Nature 410: 37–40.

    Article  CAS  PubMed  Google Scholar 

  • Cher M, Biliran Jr HR, Bhagat S, Meng Y, Che M, Lockett J et al. (2003). Maspin expression inhibits osteolysis, tumor growth, and angiogenesis in a model of prostate cancer bone metastasis. Proc Natl Acad Sci USA 10: 7847–7852.

    Article  Google Scholar 

  • Donehower LA, Harvey M, Slagle BL, McArthur MJ, Montgomery Jr CA, Butel JS et al. (1992). Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356: 215–221.

    Article  CAS  PubMed  Google Scholar 

  • Fan W, Jin S, Tong T, Zhao H, Fan F, Antinore MJ et al. (2002). BRCA1 regulates GADD45 through its interactions with the OCT-1 and CAAT motifs. J Biol Chem 277: 8061–8067.

    Article  CAS  PubMed  Google Scholar 

  • Gupta S, Campbell D, Dérijard B, Davis RJ . (1995). Transcription factor ATF2 regulation by the JNK signal transduction pathway. Science 267: 389–393.

    Article  CAS  PubMed  Google Scholar 

  • Harkin DP, Bean JM, Miklos D, Song YH, Truong VB, Englert C et al. (1999). Induction of GADD45 and JNK/SAPK-dependent apoptosis following inducible expression of BRCA1. Cell 97: 575–586.

    Article  CAS  PubMed  Google Scholar 

  • Hollander MC, Sheikh MS, Bulavin DV, Lundgren K, Augeri-Henmueller L, Shehee R et al. (1999). Genomic instability in Gadd45α-deficient mice. Nat Genet 23: 176–184.

    Article  CAS  PubMed  Google Scholar 

  • Kastan MB, Zhan Q, el-Deiry WS, Carrier F, Jacks T, Walsh WV et al. (1992). A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Cell 71: 587–597.

    Article  CAS  PubMed  Google Scholar 

  • Li S, Ting NS, Zheng L, Chen PL, Ziv Y, Shiloh Y et al. (2000). Functional link of BRCA1 and ataxia telangiectasia gene product in DNA damage response. Nature 406: 210–215.

    Article  CAS  PubMed  Google Scholar 

  • Liu J, Yin S, Reddy N, Spencer C, Sheng S . (2004). Bax mediates the apoptosis-sensitizing effect of maspin. Cancer Res 64: 1703–1711.

    Article  CAS  PubMed  Google Scholar 

  • Maekawa T, Bernier F, Sato M, Nomura S, Singh M, Inoue Y et al. (1999). Mouse ATF-2 null mutants display features of a severe type of meconium aspiration syndrome. J Biol Chem 274: 17813–17819.

    Article  CAS  PubMed  Google Scholar 

  • Maekawa T, Sakura H, Kanei-Ishii C, Sudo T, Yoshimura T, Fujisawa J et al. (1989). Leucine zipper structure of the protein CRE-BP1 binding to the cyclic AMP response element in brain. EMBO J 8: 2023–2028.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maekawa T, Shinagawa T, Sano Y, Sakuma T, Nomura S, Nagasaki K et al. (2007). Reduced levels of ATF-2 predispose mice to mammary tumors. Mol Cell Biol 27: 1730–1744.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mita H, Tsutsui J, Takekawa M, Witten EA, Saito H . (2002). Regulation of MTK1/MEKK4 kinase activity by its N-terminal autoinhibitory domain and GADD45 binding. Mol Cell Biol 22: 4544–4555.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Osada S, Yamamoto H, Nishihara T, Imagawa M . (1996). DNA binding specificity of the CCAAT/enhancer-binding protein transcription factor family. J Biol Chem 271: 3891–3896.

    Article  CAS  PubMed  Google Scholar 

  • Takahashi S, Saito S, Ohtani N, Sakai T . (2001). Involvement of the Oct-1 regulatory element of the gadd45 promoter in the p53-independent response to ultraviolet irradiation. Cancer Res 61: 1187–1195.

    CAS  PubMed  Google Scholar 

  • Takekawa M, Saito H . (1998). A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK. Cell 95: 521–530.

    Article  CAS  PubMed  Google Scholar 

  • Venkitaraman AR . (2002). Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell 108: 171–182.

    Article  CAS  PubMed  Google Scholar 

  • Xu X, Wagner KU, Larson D, Weaver Z, Li C, Ried T et al. (1999). Conditional mutation of Brca1 in mammary epithelial cells results in blunted ductal morphogenesis and tumour formation. Nature Genet 22: 37–43.

    Article  CAS  PubMed  Google Scholar 

  • Zhang M, Maass N, Magit D, Sager R . (1997). Transactivation through Ets and Ap1 transcription sites determines the expression of the tumor-suppressing gene maspin. Cell Growth Differ 8: 179–186.

    CAS  PubMed  Google Scholar 

  • Zhang M, Volpert O, Shi YH, Bouck N . (2000). Maspin is an angiogenesis inhibitor. Nat Med 6: 196–199.

    Article  PubMed  Google Scholar 

  • Zou Z, Anisowicz A, Hendrix MJ, Thor A, Neveu M, Sheng S et al. (1994). Maspin, a serpin with tumor-suppressing activity in human mammary epithelial cells. Science 263: 526–529.

    Article  CAS  PubMed  Google Scholar 

  • Zou Z, Gao C, Nagaich AK, Connell T, Saito S, Moul JW et al. (2000). p53 regulates the expression of the tumor suppressor gene maspin. J Biol Chem 275: 6051–6054.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We are grateful to S Aizawa for the p53+/− mice, T Sakai for the pGADD45-Luc construct, M Imagawa for the NF-IA1 cDNA, RG Roeder for the Oct-1 cDNA and members of the Experimental Animal Division of RIKEN Tsukuba Institute for maintaining the mice. This work was supported in part by Grants-in-Aid for Scientific Research and by grants of the Genome Network Project from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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Correspondence to T Maekawa or S Ishii.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Maekawa, T., Sano, Y., Shinagawa, T. et al. ATF-2 controls transcription of Maspin and GADD45α genes independently from p53 to suppress mammary tumors. Oncogene 27, 1045–1054 (2008). https://doi.org/10.1038/sj.onc.1210727

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