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DNA (cytosine-5)-methyltransferase 1 as a mediator of mutant p53-determined p16ink4A down-regulation

  • Original Paper
  • Published:
Journal of Biomedical Science

Abstract

In cancer, gene silencing via hypermethylation is as common as genetic mutations in p53. Understanding the relationship between mutant p53 and hypermethylation of other tumor suppressor genes is essential when elucidate mechanisms of tumor development. In this study, two isogenic human B lymphoblast cell lines with different p53 status include TK6 containing wild-type p53 and WTK1 with mutant p53 were used and contrasted. Lower levels of p16ink4A protein were detected in WTK1 cells than in TK6 cells, which were accompanied by increased DNA (cytosine-5)-methyltransferase 1 (DNMT1) gene expression as well as hypermethylation of the p16 ink4A promoter. siRNA experiments to transiently knock down wild-type p53 in TK6 cells resulted in increase of DNMT1 expression as well as decrease of p16ink4A protein. Conversely, siRNA knockdown of mutant p53 in WTK1 cells did not alter either DNMT1 or p16ink4A protein levels. Furthermore, loss of suppression function of mutant p53 to DNMT1 in WTK1 was caused by the attenuation of its binding ability to the DNMT1 promoter. In summary, we provide evidences to elucidate the relationship between mutant p53 and DNMT1. Our results indicate that mutant p53 loses its ability to suppress DNMT1 expression, and thus enhances methylation levels of the p16 ink4A promoter and subsequently down-regulates p16ink4A protein.

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Acknowledgments

This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, DEFG02-03ER63635 (EYC) from the Department of Energy, and 95HM0032 (EYC) and 95HM0033195R0066-BM01-01 (EYC) from National Taiwan University.

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Authors and Affiliations

  1. Radiation Biology and Oncology Branches, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA

    Zhanjun Guo, Mong-Hsun Tsai, Xing Lv, David Gius, James B. Mitchell & Eric Y. Chuang

  2. Department of Gastroenterology and Hepatology, The Fourth Hospital, Hebei Medical University, Shijiazhuang, China

    Zhanjun Guo

  3. Institute of biotechnology, College of Bio-Resources and Agriculture, National Taiwan University, Taipei, Taiwan

    Mong-Hsun Tsai

  4. Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, National Institutes of Health, Frederick, MD, 21702, USA

    Yih-Horng Shiao

  5. Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, No. 1 Section 4 Roosevelt Road, Taipei, Taiwan

    Li-Han Chen & Eric Y. Chuang

  6. Departments of Electrical Engineering and Life Science, Graduate Institute of Epidemiology, National Taiwan University, Taipei, Taiwan

    Li-Han Chen & Eric Y. Chuang

  7. Research Center For Medical Excellence, National Taiwan University, Taipei, Taiwan

    Li-Han Chen & Eric Y. Chuang

  8. Division of Neurosciences, Walter Reed Army Institute of Research, Silver Spring, MD, 20910, USA

    Mei-Ling Wei

  9. Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA, 02115, USA

    John B. Little

Authors
  1. Zhanjun Guo
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  2. Mong-Hsun Tsai
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  3. Yih-Horng Shiao
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  4. Li-Han Chen
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  5. Mei-Ling Wei
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  6. Xing Lv
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  7. David Gius
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  8. John B. Little
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  9. James B. Mitchell
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  10. Eric Y. Chuang
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Corresponding author

Correspondence to Eric Y. Chuang.

Additional information

Z. Guo and M.-H. Tsai contributed equally to this work.

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Guo, Z., Tsai, MH., Shiao, YH. et al. DNA (cytosine-5)-methyltransferase 1 as a mediator of mutant p53-determined p16ink4A down-regulation. J Biomed Sci 15, 163–168 (2008). https://doi.org/10.1007/s11373-007-9222-y

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  • DOI: https://doi.org/10.1007/s11373-007-9222-y

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