The Regulation of p53 by E3 ligases MDM2 and CHIP in Breast Cancer: Analysis of the Role of Hsp70 and Hsp90

Abstract

Tumor suppressor p53 is commonly mutated in breast cancer. Mutant p53 protein is highly stable and oncogenic. This study aims to understand the underlying mechanism of the regulation and stabilization of mutant p53 protein particularly folded mutant p53 R280K. The data showed a possible association between the levels of mutant p53 and the E3 ligases CHIP and MDM2 in various breast cancer cell lines. The data also showed that p53 R280K could be induced in response to 5-FU induced stress in manners similar to the WT p53. Afterward, this study analyzed the role of Hsp90 and Hsp70 in the stabilization of p53 (R280K) through the siRNA-mediated-depletion of Hsp90 and Hsp70. The decrease of HSP90 expression revealed a significant degradation of mutant p53 protein, yet failed to affect the protein levels of CHIP and MDM2. Similar observations found upon depletion of Hsp70 concerning mutant p53 and CHIP. However, Hsp70 depletion activated the expression of MDM2. In contrast, the suppression of Hsp90 rather than Hsp70 elevated the expression of both WT p53 and MDM2. These findings confirm the importance of Hsp70 and Hsp90 in the stabilization of mutant p53 and suggest a mechanism in which Hsp70 mediates the stabilization of folded mutant p53 through the inactivation of MDM2 expression.