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BMC Mol Biol. 2007 May 21;8:37.

Rad9 modulates the P21WAF1 pathway by direct association with p53.

Author information

1
Department of Otolaryngology-Head and Neck Surgery, Jichi Medical University School of Medicine, Tochigi, Japan. kazu-ish@jichi.ac.jp <kazu-ish@jichi.ac.jp>

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.

PMID:
17511890
PMCID:
PMC1885445
DOI:
10.1186/1471-2199-8-37
[Indexed for MEDLINE]
Free PMC Article

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