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

Zhanjun Guo, Mong Hsun Tsai, Yih Horng Shiao, Li Han Chen, Mei Ling Wei, Xing Lv, David Gius, John B. Little, James B. Mitchell, Eric Y. Chuang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)163-168
Number of pages6
JournalJournal of Biomedical Science
Volume15
Issue number2
DOIs
StatePublished - Mar 2008

Keywords

  • Chromatin immunoprecipitation
  • DNMT1
  • Methylation-specific polymerase chain reaction
  • Small interfering RNA
  • p53

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology
  • Biochemistry, medical
  • Pharmacology (medical)

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