HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation

HER-2/neu amplification or overexpression can make cancer cells resistant t o apoptosis and promotes their growth. p53 is crucial in regulating cell gr owth and apoptosis, and is often mutated or deleted in many types of tumour . Moreover, many turnours with a wild-type gene for p53 do not have normal p53 function, suggesting that some oncogenic signals suppress the function of p53. In this study, we show that HER-2/neu-mediated resistance to DNA-da maging agents requires the activation of Akt, which enhances MDM2-mediated ubiquitination and degradation of p53. Akt physically associates with MDM2 and phosphorylates it at Ser166 and Ser186. Phosphorylation of MDM2 enhance s its nuclear localization and its interaction with p300, and inhibits its interaction with P19(ARF), thus increasing p53 degradation. Our study indic ates that blocking the Akt pathway mediated by HER-2/neu would increase the cytotoxic effect of DNA-damaging drugs in tumour cells with wild-type p53.