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Bach1 inhibits oxidative stress–induced cellular senescence by impeding p53 function on chromatin

Nature Structural & Molecular Biology volume 15, pages 1246–1254 (2008)Cite this article

Abstract

Cellular senescence is one of the key strategies to suppress expansion of cells with mutations. Senescence is induced in response to genotoxic and oxidative stress. Here we show that the transcription factor Bach1 (BTB and CNC homology 1, basic leucine zipper transcription factor 1), which inhibits oxidative stress-inducible genes, is a crucial negative regulator of oxidative stress–induced cellular senescence. Bach1-deficient murine embryonic fibroblasts showed a propensity to undergo more rapid and profound p53-dependent premature senescence than control wild-type cells in response to oxidative stress. Bach1 formed a complex that contained p53, histone deacetylase 1 and nuclear co-repressor N-coR. Bach1 was recruited to a subset of p53 target genes and contributed to impeding p53 action by promoting histone deacetylation. Because Bach1 is regulated by oxidative stress and heme, our data show that Bach1 connects oxygen metabolism and cellular senescence as a negative regulator of p53.

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Figure 1: Bach1 deficiency resulted in reduced proliferation in MEFs.
Figure 2: Oxidative stress–induced premature senescence in Bach1−/− (KO) MEFs.
Figure 3: p53-dependent senescence in Bach1−/− MEFs.
Figure 4: Inhibition of Ras-induced cellular senescence in MEFs by Bach1.
Figure 5: Bach1 repressed a subset of p53 target genes.
Figure 6: Purification of the Bach1 complex.
Figure 7: Recruitment of Bach1 to p53 target genes.
Figure 8: Bach1 facilitates repression of target genes by recruiting Hdac1.

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References

  1. Braig, M. et al. Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 436, 660–665 (2005).

    Article  CAS  PubMed  Google Scholar 

  2. Chen, Z. et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436, 725–730 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Michaloglou, C. et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436, 720–724 (2005).

    Article  CAS  PubMed  Google Scholar 

  4. Collado, M. et al. Tumour biology: senescence in premalignant tumours. Nature 436, 642 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Ben-Porath, I. & Weinberg, R.A. The signals and pathways activating cellular senescence. Int. J. Biochem. Cell Biol. 37, 961–976 (2005).

    Article  CAS  PubMed  Google Scholar 

  6. Brown, J.P., Wei, W. & Sedivy, J.M. Bypass of senescence after disruption of p21CIP1/WAF1 gene in normal diploid human fibroblasts. Science 277, 831–834 (1997).

    Article  CAS  PubMed  Google Scholar 

  7. Kortlever, R.M., Higgins, P.J. & Bernards, R. Plasminogen activator inhibitor-1 is a critical downstream target of p53 in the induction of replicative senescence. Nat. Cell Biol. 8, 878–884 (2006).

    Article  Google Scholar 

  8. Kubbutat, M.H., Jones, S.N. & Vousden, K.H. Regulation of p53 stability by MDM2. Nature 387, 299–303 (1997).

    Article  CAS  PubMed  Google Scholar 

  9. Honda, R., Tanaka, H. & Yasuda, H. Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett. 420, 25–27 (1997).

    Article  CAS  PubMed  Google Scholar 

  10. Shieh, S.Y., Ikeda, M., Taya, Y. & Prives, C. DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2. Cell 91, 325–334 (1997).

    Article  CAS  PubMed  Google Scholar 

  11. Finkel, T. Oxidant signals and oxidative stress. Curr. Opin. Cell Biol. 15, 247–254 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Parrinello, S. et al. Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts. Nat. Cell Biol. 5, 741–747 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Harvey, M. et al. In vitro growth characteristics of embryo fibroblasts isolated from p53-deficient mice. Oncogene 8, 2457–2467 (1993).

    CAS  PubMed  Google Scholar 

  14. Oyake, T. et al. Bach proteins belong to a novel family of BTB-basic leucine zipper transcription factors that interact with MafK and regulate transcription through the NF-E2 site. Mol. Cell. Biol. 16, 6083–6095 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Igarashi, K. & Sun, J. The heme-Bach1 pathway in the regulation of oxidative stress response and erythroid differentiation. Antioxid. Redox Signal. 8, 107–118 (2006).

    Article  CAS  PubMed  Google Scholar 

  16. Sun, J. et al. Hemoprotein Bach1 regulates enhancer availability of heme oxygenase-1 gene. EMBO J. 21, 5216–5224 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Omura, S. et al. Effects of genetic ablation of bach1 upon smooth muscle cell proliferation and atherosclerosis after cuff injury. Genes Cells 10, 277–285 (2005).

    Article  CAS  PubMed  Google Scholar 

  18. Dimri, G.P. et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc. Natl. Acad. Sci. USA 92, 9363–9367 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Rogakou, E.P., Pilch, D.R., Orr, A.H., Ivanova, V.S. & Bonner, W.M. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J. Biol. Chem. 273, 5858–5868 (1998).

    Article  CAS  PubMed  Google Scholar 

  20. Lowe, S.W., Cepero, E. & Evan, G. Intrinsic tumour suppression. Nature 432, 307–315 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Gire, V. & Wynford-Thomas, D. Reinitiation of DNA synthesis and cell division in senescent human fibroblasts by microinjection of anti-p53 antibodies. Mol. Cell. Biol. 18, 1611–1621 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Campisi, J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120, 513–522 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Serrano, M., Lin, A.W., McCurrach, M.E., Beach, D. & Lowe, S.W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593–602 (1997).

    Article  CAS  PubMed  Google Scholar 

  24. Attardi, L.D. et al. PERP, an apoptosis-associated target of p53, is a novel member of the PMP-22/gas3 family. Genes Dev. 14, 704–718 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Clarke, A.R. et al. Thymocyte apoptosis induced by p53-dependent and independent pathways. Nature 362, 849–852 (1993).

    Article  CAS  PubMed  Google Scholar 

  26. Wei, C.L. et al. A global map of p53 transcription-factor binding sites in the human genome. Cell 124, 207–219 (2006).

    Article  CAS  PubMed  Google Scholar 

  27. Tanaka, H. et al. A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage. Nature 404, 42–49 (2000).

    Article  CAS  PubMed  Google Scholar 

  28. Zoidl, G. et al. Influence of elevated expression of rat wild-type PMP22 and its mutant PMP22Trembler on cell growth of NIH3T3 fibroblasts. Cell Tissue Res. 287, 459–470 (1997).

    Article  CAS  PubMed  Google Scholar 

  29. Gu, W. & Roeder, R.G. Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 90, 595–606 (1997).

    Article  CAS  PubMed  Google Scholar 

  30. Ikura, T. et al. Involvement of the TIP60 histone acetylase complex in DNA repair and apoptosis. Cell 102, 463–473 (2000).

    Article  CAS  PubMed  Google Scholar 

  31. Fujiwara, K.T., Kataoka, K. & Nishizawa, M. Two new members of the maf oncogene family, mafK and mafF, encode nuclear b-Zip proteins lacking putative trans-activator domain. Oncogene 8, 2371–2380 (1993).

    CAS  PubMed  Google Scholar 

  32. Yamasaki, C., Tashiro, S., Nishito, Y., Sueda, T. & Igarashi, K. Dynamic cytoplasmic anchoring of the transcription factor Bach1 by intracellular hyaluronic acid binding protein IHABP. J. Biochem. 137, 287–296 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Heinzel, T. et al. A complex containing N-CoR, mSin3 and histone deacetylase mediates transcriptional repression. Nature 387, 43–48 (1997).

    Article  CAS  PubMed  Google Scholar 

  34. Alland, L. et al. Role for N-CoR and histone deacetylase in Sin3-mediated transcriptional repression. Nature 387, 49–55 (1997).

    Article  CAS  PubMed  Google Scholar 

  35. Reczek, E.E., Flores, E.R., Tsay, A.S., Attardi, L.D. & Jacks, T. Multiple response elements and differential p53 binding control Perp expression during apoptosis. Mol. Cancer Res. 1, 1048–1057 (2003).

    CAS  PubMed  Google Scholar 

  36. Kaeser, M.D. & Iggo, R.D. Chromatin immunoprecipitation analysis fails to support the latency model for regulation of p53 DNA binding activity in vivo. Proc. Natl. Acad. Sci. USA 99, 95–100 (2002).

    Article  CAS  PubMed  Google Scholar 

  37. Sun, J. et al. Heme regulates the dynamic exchange of Bach1 and NF-E2-related factors in the Maf transcription factor network. Proc. Natl. Acad. Sci. USA 101, 1461–1466 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. de Stanchina, E. et al. PML is a direct p53 target that modulates p53 effector functions. Mol. Cell 13, 523–535 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Pearson, M. & Pelicci, P.G. PML interaction with p53 and its role in apoptosis and replicative senescence. Oncogene 20, 7250–7256 (2001).

    Article  CAS  PubMed  Google Scholar 

  40. Yang, A. et al. p63, a p53 homolog at 3q27–29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. Mol. Cell 2, 305–316 (1998).

    Article  CAS  PubMed  Google Scholar 

  41. Yang, A. et al. Relationships between p63 binding, DNA sequence, transcription activity, and biological function in human cells. Mol. Cell 24, 593–602 (2006).

    Article  CAS  PubMed  Google Scholar 

  42. Hublitz, P. et al. NIR is a novel INHAT repressor that modulates the transcriptional activity of p53. Genes Dev. 19, 2912–2924 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Sablina, A.A. et al. The antioxidant function of the p53 tumor suppressor. Nat. Med. 11, 1306–1313 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ishikawa, M., Numazawa, S. & Yoshida, T. Redox regulation of the transcriptional repressor Bach1. Free Radic. Biol. Med. 38, 1344–1352 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Igarashi, K. et al. Regulation of transcription by dimerization of erythroid factor NF-E2 p45 with small Maf proteins. Nature 367, 568–572 (1994).

    Article  CAS  PubMed  Google Scholar 

  46. Igarashi, K. et al. Multivalent DNA binding complex generated by small Maf and Bach1 as a possible biochemical basis for β-globin locus control region complex. J. Biol. Chem. 273, 11783–11790 (1998).

    Article  CAS  PubMed  Google Scholar 

  47. Ito, A. et al. p300/CBP-mediated p53 acetylation is commonly induced by p53-activating agents and inhibited by MDM2. EMBO J. 20, 1331–1340 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank T. Jacks (Massachusetts Institute of Technology), T.P. Yao (Duke University), K. Tanimoto (Hiroshima University), H. Ogawa (National Institute of Basic Biology), N. Tanaka (Nippon Medical School) and K. Umesono for providing plasmids and antibodies; Y. Ishikawa and K. Nakayama (Tohoku University) for providing p53−/− MEFs; and M. Katsuki (National Institute of Basic Biology) for providing Trp53−/− mice. We also thank M. Kobayashi and Y. Taya for comments on the manuscript; S. Tashiro and T. Ide for valuable advice to initiate the project; M. Ikura for help in cell culturing; and M. Yoshizumi and N. Tanaka for advice. This work was supported by Grants-in-aid and the Network Medicine Global-COE Program from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and grants from the Uehara Foundation, the Takeda Foundation and the Astellas Foundation for Research on Metabolic Disorders.

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  1. Yoshihiro Dohi

    Present address: Present address: Department of Cardiovascular Medicine, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima 734-8551, Japan.,

Authors and Affiliations

  1. Department of Biochemistry, Tohoku University Graduate School of Medicine, Seiryo-machi 2-1, Sendai, 980-8575, Japan

    Yoshihiro Dohi, Tsuyoshi Ikura, Yasutake Katoh, Kazushige Ota, Ayako Nakanome, Akihiko Muto & Kazuhiko Igarashi

  2. Department of Cardiovascular Physiology and Medicine, Hiroshima University Graduate School of Biomedical Science, Kasumi 1-2-3, Hiroshima, 734-8551, Japan

    Yoshihiro Dohi & Shinji Omura

  3. Japanese Foundation for Cancer Research, Cancer Institute, Ariake 3-10-6, Tokyo, 135-8550, Japan

    Yutaka Hoshikawa & Tetsuo Noda

  4. Center for Medical Genomics, National Cancer Center Research Institute, 5-1-1 Tsukiji Chuo-ku, Tokyo, 104-0045, Japan

    Tsutomu Ohta

  5. Chemical Genetics Laboratory, RIKEN, Wako, 351-0198, Saitama, Japan

    Akihiro Ito & Minoru Yoshida

  6. Japan Science and Technology Corporation (JST), CREST Research Project, Kawasaki, 332-0012, Saitama, Japan

    Minoru Yoshida

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Contributions

Y.D., T.I., Y.K., K.O., A.N., A.M., S.O., A.I. and M.Y. contributed to performing and assisting with experiments; A.M. and T.O. contributed to performing gene expression profiling; Y.H. and T.N. contributed to performing MS/MS analysis; K.I. designed and conceptualized the study; Y.D., T.I., T.N. and K.I. interpreted the data and Y.D., T.I. and K.I. wrote the manuscript. All authors made comments on the manuscript.

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Correspondence to Kazuhiko Igarashi.

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Dohi, Y., Ikura, T., Hoshikawa, Y. et al. Bach1 inhibits oxidative stress–induced cellular senescence by impeding p53 function on chromatin. Nat Struct Mol Biol 15, 1246–1254 (2008). https://doi.org/10.1038/nsmb.1516

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