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- Title
Rad9 modulates the P21<sup>WAF1</sup> pathway by direct association with p53.
- Authors
Ishikawa, Kazuhiro; Ishii, Hideshi; Murakumo, Yoshiki; Mimori, Koshi; Kobayashi, Masahiko; Yamamoto, Ken-ichi; Mori, Masaki; Nishino, Hiroshi; Furukawa, Yusuke; Ichimura, Keiichi
- Abstract
Background: Previous studies suggest that human RAD9 (hRad9), encoding a DNA damage checkpoint molecule, which is frequently amplified in epithelial tumor cells of breast, lung, head and neck cancer, participates in regulation of the tumor suppressor p53-dependent transactivation of pro-survival P21WAF1. This study examined the exact mechanism of the hRad9 function, especially through the phosphorylation of the C-terminus, in the transcription regulation of P21WAF1. Results: The transfection of phosphorylation-defective hRAD9 mutants of C-terminus resulted in reduction of the p53-dependent P21WAF1 transactivation; the knockdown of total hRad9 elicited an increased P21WAF1 mRNA expression. Immunoprecipitation and a ChIP assay showed that hRad9 and p53 formed a complex and both were associated with two p53-consensus DNA-binding sequences in the 5′ region of P21WAF1 gene. The association was reduced in the experiment of phosphorylation-defective hRAD9 mutants. Conclusion: The present study indicates the direct involvement of hRad9 in the p53-dependent P21WAF1 transcriptional mechanism, presumably via the phosphorylation sites, and alterations of the hRad9 pathway might therefore contribute to the perturbation of checkpoint activation in cancer cells.
- Subjects
DNA damage; CANCER cells; PHOSPHORYLATION; GENETIC transcription; MOLECULAR biology; MESSENGER RNA; GENE expression; CELL cycle
- Publication
BMC Molecular Biology, 2007, Vol 8, p1
- ISSN
1471-2199
- Publication type
Article
- DOI
10.1186/1471-2199-8-37