Abrogation of the Transactivation Activity of p53 by BCCIP Down-regulation

Xiangbing Meng,Zhihe Liu,Zhiyuan Shen,Jingyin Yue

doi:10.1074/jbc.m607520200

Xiangbing Meng, Zhihe Liu + Show 2 more

Open Access

https://doi.org/10.1074/jbc.m607520200

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Abstract

The tumor suppression function of p53 is mostly conferred by its transactivation activity, which is inactivated by p53 mutations in approximately 50% of human cancers. In cancers harboring wild type p53, the p53 transactivation activity may be compromised by other mechanisms. Identifying the mechanisms by which wild type p53 transactivation activity can be abrogated may provide insights into the molecular etiology of cancers harboring wild type p53. In this report, we show that BCCIP, a BRCA2 and CDKN1A-interacting protein, is required for the transactivation activity of wild type p53. In p53 wild type cells, BCCIP knock down by RNA interference diminishes the transactivation activity of p53 without reducing the p53 protein level, inhibits the binding of p53 to the promoters of p53 target genes p21 and HDM2, and reduces the tetrameric formation of p53. These data demonstrate a critical role of BCCIP in maintaining the transactivation activity of wild type p53 and further suggest down-regulation of BCCIP as a novel mechanism to impair the p53 function in cells harboring wild type p53.

Highlights

Mutations in p53 are found in ϳ50% of all human cancers, and inactivation of p53 leads to cancer predisposition in animal models [7]
We found that down-regulation of BCCIP overrides the transcriptional activity of wild type p53, suggesting a novel mechanism by which the p53 transactivation function can be compromised
We showed that the induction of p21 by BCCIP overexpression is dependent on p53 and that the p53 transactivation activity is enhanced by BCCIP overexpression [15]

Summary

Introduction

Mutations in p53 are found in ϳ50% of all human cancers, and inactivation of p53 leads to cancer predisposition in animal models [7]. HDM2 but p53 protein level was not reduced (Fig. 1B), suggesting that the transcription activity of p53 in BCCIP knockdown cells is impaired. In these BCCIP knockdown cells, we observed significant down-regulation of p21 and HDM2 proteins (Fig. 1C), p53 expression increased.

Results

Conclusion