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DNA (cytosine-5)-methyltransferase 1 as a mediator of mutant p53-determined p16(ink4A) down-regulation

  1. Author:
    Guo, Z. J.
    Tsai, M. H.
    Shiao, Y. H.
    Chen, L. H.
    Wei, M. L.
    Lv, X.
    Gius, D.
    Little, J. B.
    Mitchell, J. B.
    Chuang, E. Y.

  2. Author Address

    Chen, Li-Han, Chuang, Eric Y.] Natl Taiwan Univ, Grad Inst Biomed Elect & Bioinformat, Taipei 10764, Taiwan. [Guo, Zhanjun, Tsai, Mong-Hsun, Lv, Xing, Gius, David, Mitchell, James B.; Chuang, Eric Y.] NCI, Radiat Biol & Oncol Branches, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Guo, Zhanjun] Hebei Med Univ, Fourth Hosp, Dept Gastroenterol & Hepatol, Shijiazhuang, Taiwan. [Tsai, Mong-Hsun] Natl Taiwan Univ, Inst Biotechnol, Coll Bioesources & Agr, Taipei 10764, Taiwan. [Shiao, Yih-Horng] NCI, Comparat Carcinogenesis Lab, NIH, Frederick, MD 21702 USA. [Chen, Li-Han, Chuang, Eric Y.] Natl Taiwan Univ, Dept Elect Engn, Grad Inst Epidemiol, Taipei 10764, Taiwan. [Chen, Li-Han, Chuang, Eric Y.] Natl Taiwan Univ, Dept Life Sci, Grad Inst Epidemiol, Taipei 10764, Taiwan. [Chen, Li-Han, Chuang, Eric Y.] Natl Taiwan Univ, Res Ctr Med Excellence, Taipei 10764, Taiwan. [Wei, Mei-Ling] Walter Reed Army Inst Res, Div Neurosci, Silver Spring, MD 20910 USA. [Mitchell, James B.] Harvard Univ, Sch Publ Hlth, Dept Genet & Complex Dis, Boston, MA 02115 USA.
    1. Year: 2008
  2. Journal: Journal of Biomedical Science
    1. 15
    2. 2
    3. Pages: 163-168
  4. Type of Article: Article
  1. 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 p16(ink4A) 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 p16(ink4A) protein. Conversely, siRNA knockdown of mutant p53 in WTK1 cells did not alter either DNMT1 or p16(ink4A) 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 p16(ink4A) protein.

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External Sources

  1. PMID: 18038118

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