Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Bcl-2 expression suppresses mismatch repair activity through inhibition of E2F transcriptional activity

Nature Cell Biology volume 7, pages 137–147 (2005)Cite this article

Abstract

Bcl-2 stimulates mutagenesis after the exposure of cells to DNA-damaging agents. However, the biological mechanisms of Bcl-2-mediated mutagenesis have remained largely obscure. Here we demonstrate that the Bcl-2-mediated suppression of hMSH2 expression results in a reduced cellular capacity to repair mismatches. The pathway linking Bcl-2 expression to the suppression of mismatch repair (MMR) activity involves the hypophosphorylation of pRb, and then the enhancement of the E2F–pRb complex. This is followed by a decrease in hMSH2 expression. MMR has a key role in protection against deleterious mutation accumulation and in maintaining genomic stability. Therefore, the decreased MMR activity by Bcl-2 may be an underlying mechanism for Bcl-2-promoted oncogenesis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Bcl-2 stimulates MNNG-induced mutagenesis.
Figure 2: Expression of Bcl-2 leads to downregulation of hMSH2 mRNA and hMSH2 protein levels.
Figure 3: Bcl-2 expression suppresses MMR activity.
Figure 4: Expression of Bcl-2 results in hypophosphorylation of pRb.
Figure 5: Bcl-2 suppresses hMSH2 expression by inhibiting E2F activity.
Figure 6: siRNA-mediated down-regulation of E2F1 leads to a decrease in hMSH2 expression and MMR activity.
Figure 7: MMR activities in human B cell lymphoma cell lines.
Figure 8: Down-regulation of Cdk2 kinase activity by Bcl-2.

Similar content being viewed by others

References

  1. Tsujimoto, Y., Cossman, J., Jaffe, E. & Croce, C. M. Involvement of the bcl-2 gene in human follicular lymphoma. Science 228, 1440–1443 (1985).

    Article  CAS  PubMed  Google Scholar 

  2. McDonnell, T. J. & Korsmeyer, S. J. Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t(14;18). Nature 349, 254–256 (1991).

    Article  CAS  PubMed  Google Scholar 

  3. Binder, C. et al. Bcl-2 protein expression in breast cancer in relation to established prognostic factors and other clinicopathological variables. Ann. Oncol. 6, 1005–1010 (1995).

    Article  CAS  PubMed  Google Scholar 

  4. Kaklamanis, L. et al. Early expression of bcl-2 protein in the adenoma-carcinoma sequence of colorectal neoplasia. J. Pathol. 179, 10–14 (1996).

    Article  CAS  PubMed  Google Scholar 

  5. Crowson, A. N., Magro, C. M., Kadin, M. E. & Stranc, M. Differential expression of the bcl-2 oncogene in human basal cell carcinoma. Hum. Pathol. 27, 355–359 (1996).

    Article  CAS  PubMed  Google Scholar 

  6. Yin, D. X. & Schimke, R. T. Inhibition of apoptosis by overexpressing Bcl-2 enhances gene amplification by a mechanism independent of aphidicolin pretreatment. Proc. Natl Acad. Sci. USA 93, 3394–3398 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kuo, M. L., Shiah, S. G., Wang, C. J. & Chuang, S. E. Suppression of apoptosis by Bcl-2 to enhance benzene metabolites-induced oxidative DNA damage and mutagenesis: A possible mechanism of carcinogenesis. Mol. Pharmacol. 55, 894–901 (1999).

    CAS  PubMed  Google Scholar 

  8. Liu, Y., Naumovski, L. & Hanawalt, P. Nucleotide excision repair capacity is attenuated in human promyelocytic HL60 cells that overexpress BCL2. Cancer Res. 57, 1650–1653 (1997).

    CAS  PubMed  Google Scholar 

  9. Saintigny, Y., Dumay, A., Lambert, S. & Lopez, B. S. A novel role for the Bcl-2 protein family: specific suppression of the RAD51 recombination pathway. EMBO J. 20, 2596–2607 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Mitra, S. & Kaina, B. Regulation of repair of alkylation damage in mammalian genomes. Prog. Nucleic Acid Res. Mol. Biol. 44, 109–142 (1993).

    Article  CAS  PubMed  Google Scholar 

  11. Pegg, A. E. & Byers, T. L. Repair of DNA containing O6-alkylguanine. FASEB J. 6, 2302–2310 (1992).

    Article  CAS  PubMed  Google Scholar 

  12. Yang, J. L., Hu, M. C. & Wu, C. W. Novel mutational spectrum induced by N-methyl-N′-nitro-N-nitrosoguanidine in the coding region of the hypoxanthine (guanine) phosphoribosyltransferase gene in diploid human fibroblasts. J. Mol. Biol. 221, 421–430 (1991).

    Article  CAS  PubMed  Google Scholar 

  13. Duckett, D. R. et al. Human MutSα recognizes damaged DNA base pairs containing O6-methylguanine, O4-methylthymine, or the cisplatin-d(GpG) adduct. Proc. Natl Acad. Sci. USA 93, 6443–6447 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Chang, D. K., Ricciardiello, L., Goel, A., Chang, C. L. & Boland, C. R. Steady-state regulation of the human DNA mismatch repair system. J. Biol. Chem. 275, 18424–18431 (2000).

    Article  CAS  PubMed  Google Scholar 

  15. Jiricny, J. Replication errors: challenging the genome. EMBO J. 17, 6427–6436 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Modrich, P. & Lahue, R. Mismatch repair in replication fidelity, genetic recombination, and cancer biology. Annu. Rev. Biochem. 65, 101–133 (1996).

    Article  CAS  PubMed  Google Scholar 

  17. Hsieh, P. Molecular mechanisms of DNA mismatch repair. Mutat. Res. 486, 71–87 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Huang, D. C., O'Reilly, L. A., Strasser, A. & Cory, S. The anti-apoptosis function of Bcl-2 can be genetically separated from its inhibitory effect on cell cycle entry. EMBO J. 16, 4628–4638 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yin, X. M., Oltvai, Z. N. & Korsmeyer, S. J. BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax. Nature 369, 321–323 (1994).

    Article  CAS  PubMed  Google Scholar 

  20. Adams, J. M. & Cory, S. The Bcl-2 protein family: arbiters of cell survival. Science 281, 1322–1326 (1998).

    Article  CAS  PubMed  Google Scholar 

  21. Helin, K., Harlow, E. & Fattaey, A. Inhibition of E2F-1 transactivation by direct binding of the retinoblastoma protein. Mol. Cell. Biol. 13, 6501–6508 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Graninger, W. B., Seto, M., Boutain, B., Goldman, P. & Korsmeyer, S. J. Expression of Bcl-2 and Bcl-2-Ig fusion transcripts in normal and neoplastic cells. J. Clin. Invest. 80, 1512–1515 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ohtani, K., DeGregori, J. & Nevins, J. R. Regulation of the cyclin E gene by transcription factor E2F1. Proc. Natl Acad. Sci. USA 92, 12146–12150 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Vairo, G. et al. Bcl-2 retards cell cycle entry through p27Kip1, pRB relative p130, and altered E2F regulation. Mol. Cell. Biol. 20, 4745–4753 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Iwahashi, Y. et al. Promoter analysis of the human mismatch repair gene hMSH2. Gene 213, 141–147 (1998).

    Article  CAS  PubMed  Google Scholar 

  26. Polager, S., Kalma, Y., Berkovich, E. & Ginsberg, D. E2Fs up-regulate expression of genes involved in DNA replication, DNA repair and mitosis. Oncogene 21, 437–446 (2002).

    Article  CAS  PubMed  Google Scholar 

  27. Ren, B. et al. E2F integrates cell cycle progression with DNA repair, replication, and G2/M checkpoints. Genes Dev. 16, 245–256 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Chellappan, S. P., Hiebert, S., Mudryj, M., Horowitz, J. M. & Nevins, J. R. The E2F transcription factor is a cellular target for the RB protein. Cell 65, 1053–1061 (1991).

    Article  CAS  PubMed  Google Scholar 

  29. Harbour, J. W. & Dean, D. C. The Rb/E2F pathway: expanding roles and emerging paradigms. Genes Dev. 14, 2393–2409 (2000).

    Article  CAS  PubMed  Google Scholar 

  30. Brady, H. J., Gil-Gomez, G., Kirberg, J. & Berns, A. J. Bax α perturbs T cell development and affects cell cycle entry of T cells. EMBO J. 15, 6991–7001 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Linette, G. P., Li, Y., Roth, K. & Korsmeyer, S. J. Cross talk between cell death and cell cycle progression: BCL-2 regulates NFAT-mediated activation. Proc. Natl Acad. Sci. USA 93, 9545–9552 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Gil-Gomez, G., Berns, A. & Brady, H. J. A link between cell cycle and cell death: Bax and Bcl-2 modulate Cdk2 activation during thymocyte apoptosis. EMBO J. 17, 7209–7218 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lind, E. F. et al. Bcl-2-induced changes in E2F regulatory complexes reveal the potential for integrated cell cycle and cell death functions. J. Immunol. 162, 5374–5379 (1999).

    CAS  PubMed  Google Scholar 

  34. Greider, C., Chattopadhyay, A., Parkhurst, C. & Yang, E. BCL-xL and BCL2 delay Myc-induced cell cycle entry through elevation of p27 and inhibition of G1 cyclin-dependent kinases. Oncogene 21, 7765–7775 (2002).

    Article  CAS  PubMed  Google Scholar 

  35. Stein, G. H., Beeson, M. & Gordon, L. Failure to phosphorylate the retinoblastoma gene product in senescent human fibroblasts. Science 249, 666–669 (1990).

    Article  CAS  PubMed  Google Scholar 

  36. Krtolica, A., Parrinello, S., Lockett, S., Desprez, P. Y. & Campisi, J. Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc. Natl Acad. Sci. USA 98, 12072–12077 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. DePinho, R. A. The age of cancer. Nature 408, 248–254 (2000).

    Article  CAS  PubMed  Google Scholar 

  38. Yamasaki, L. et al. Tumor induction and tissue atrophy in mice lacking E2F-1. Cell 85, 537–548 (1996).

    Article  CAS  PubMed  Google Scholar 

  39. de Wind, N., Dekker, M., Berns, A., Radman, M. & te Riele, H. Inactivation of the mouse Msh2 gene results in mismatch repair deficiency, methylation tolerance, hyperrecombination, and predisposition to cancer. Cell 82, 321–330 (1995).

    Article  CAS  PubMed  Google Scholar 

  40. Hemminki, A. et al. Loss of the wild type MLH1 gene is a feature of hereditary nonpolyposis colorectal cancer. Nature Genet. 8, 405–410 (1994).

    Article  CAS  PubMed  Google Scholar 

  41. Fishel, R. et al. The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 75, 1027–1038 (1993).

    Article  CAS  PubMed  Google Scholar 

  42. Drummond, J. T., Li, G. M., Longley, M. J. & Modrich, P. Isolation of an hMSH2–p160 heterodimer that restores DNA mismatch repair to tumor cells. Science 268, 1909–1912 (1995).

    Article  CAS  PubMed  Google Scholar 

  43. Vogelstein, B. & Kinzler, K. W. (eds) The Genetic Basis of Human Cancer (McGraw-Hill, New York, 1998).

    Google Scholar 

  44. Jiricny, J. & Nystrom-Lahti, M. Mismatch repair defects in cancer. Curr. Opin. Genet. Dev. 10, 157–161 (2000).

    Article  CAS  PubMed  Google Scholar 

  45. Umar, A. et al. Correction of hypermutability, N-methyl-N′-nitro-N-nitrosoguanidine resistance, and defective DNA mismatch repair by introducing chromosome 2 into human tumor cells with mutations in MSH2 and MSH6. Cancer Res. 57, 3949–3955 (1997).

    CAS  PubMed  Google Scholar 

  46. Drummond, J. T., Li, G. M., Longley, M. J. & Modrich, P. Isolation of an hMSH2–p160 heterodimer that restores DNA mismatch repair to tumor cells. Science 268, 1909–1912 (1995).

    Article  CAS  PubMed  Google Scholar 

  47. Thomas, D. C., Umar, A. & Kunkel, T. A. Measurement of heteroduplex repair in human cell extracts. Methods 7, 187–197 (1995).

    Article  CAS  Google Scholar 

  48. Takahashi, Y., Rayman, J. B. & Dynlacht, B. D. Analysis of promoter binding by the E2F and pRB families in vivo: distinct E2F proteins mediate activation and repression. Genes Dev. 14, 804–816 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Srivenugopal, K. S., Mullapudi, S. R., Shou, J., Hazra, T. K. & Ali-Osman, F. Protein phosphorylation is a regulatory mechanism for O6-alkylguanine-DNA alkyltransferase in human brain tumor cells. Cancer Res. 15, 282–287 (2000).

    Google Scholar 

Download references

Acknowledgements

This work was supported by the Ministry of Science and Technology of Korea and the Korea Science and Engineering Foundation through the Research Center for Proteineous Materials, and was supported by the Molecular and Celluar BioDiscovery Research Program grant from the Ministry of Science and Technology, South Korea. We thank J. S. Valentine (University of California) for the Bcl-2 cDNA; W. G. Kaelin Jr (Harvard Medical School, Boston) for the pCMV–E2F1-Y411C plasmid; W. Heyns (Catholic University of Leuven, Leuven, Belgium) for the E2F reporter construct; S.J. Korsmeyer (Washington University School of Medicine) for Bcl-2G145A; S. Cory and J. Adams (The Walter and Eliza Hall Institute of Medical Research, Australia) for the Bcl-2Y28A; T.H. Kim for Bcl-XL cDNA (Chosun University School of Medicine, Korea); C. Thomas and A. Kunkel (National Institutes of Health) for HCT116 and HCT116-chr3; A. L. Epstein (University of Southern California) for SU-DHL-9, SU-DHL-6 and SU-DHL-4; and R. Boland (University of California) for HEC59 and HEC59-chr2.

Author information

Authors and Affiliations

  1. Department of Pharmacology, School of medicine, Chosun University, 375 Seusuk-dong, Gwangju, 501-759, South Korea

    Cha-Kyung Youn, Hyun-Ju Cho, Soo-Hyun Kim, Hong-Beum Kim, Mi-Hwa Kim & Ho Jin You

  2. Research Center for Proteinous Materials, Chosun University, 375 Seusuk-Dong, Gwangju, 501-759, South Korea

    Cha-Kyung Youn, Hyun-Ju Cho, Soo-Hyun Kim, Hong-Beum Kim, Mi-Hwa Kim, In-Youb Chang, Jung-Sup Lee, Kyung-Soo Hahm & Ho Jin You

  3. Department of Pharmacology, School of medicine, Seoul National University, 28 Yongon-Dong, Seoul, 110-799, South Korea

    Myung-Hee Chung

Authors
  1. Cha-Kyung Youn
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hyun-Ju Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Soo-Hyun Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hong-Beum Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mi-Hwa Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. In-Youb Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jung-Sup Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Myung-Hee Chung
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kyung-Soo Hahm
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ho Jin You
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ho Jin You.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Fig S1, Fig S2, Fig S3, Fig S4 (PDF 106 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Youn, CK., Cho, HJ., Kim, SH. et al. Bcl-2 expression suppresses mismatch repair activity through inhibition of E2F transcriptional activity. Nat Cell Biol 7, 137–147 (2005). https://doi.org/10.1038/ncb1215

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb1215

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing