DNA (cytosine-5)-methyltransferase 1 as a mediator of mutant p53-determined p16ink4A down-regulation
Journal
Journal of Biomedical Science
Journal Volume
15
Journal Issue
2
Pages
163-168
Date Issued
2008
Author(s)
Guo Z
Shiao Y.-H
Wei M.-L
Lv X
Gius D
Little J.B
Mitchell J.B
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. © 2007 National Science Council.
Subjects
Chromatin immunoprecipitation; DNMT1; Methylation-specific polymerase chain reaction; p53; Small interfering RNA
SDGs
Other Subjects
cyclin dependent kinase inhibitor 2A; DNA methyltransferase 1; protein p53; small interfering RNA; article; B lymphoblast; binding affinity; cell line; down regulation; gene expression; human; human cell; methylation; mutant; priority journal; wild type
Type
journal article