Abstract
HER-2/neu amplification or overexpression can make cancer cells resistant to apoptosis and promotes their growth. p53 is crucial in regulating cell growth and apoptosis, and is often mutated or deleted in many types of tumour. Moreover, many tumours 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-damaging 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 enhances its nuclear localization and its interaction with p300, and inhibits its interaction with p19ARF, thus increasing p53 degradation. Our study indicates 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.
| Original language | English |
|---|---|
| Pages (from-to) | 973-982 |
| Number of pages | 10 |
| Journal | Nature Cell Biology |
| Volume | 3 |
| Issue number | 11 |
| DOIs | |
| State | Published - 2001 |
Bibliographical note
Funding Information:ACKNOWLEDGEMENTS We thank G. Lozano for kindly providing p53–/– MEF and p53–/–, MDM2–/– MEF cells. This work was supported by grants CA 58880, CA 77858 and CA 78633, by a SPORE grant in ovarian cancer (CA 83639) (to M.-C.H.), and by the Nellie Connally Breast Cancer Research Fund at the M. D. Anderson Cancer Center (to M.-C.H.). B.P.Z. and Y.L. are recipients of postdoctoral fellowships from US Department of Defense Breast Cancer Research Training Grant DAMD17-99-1-9264 and US Department of Defense Breast Cancer Research Program (DAMD17-01-0300), respectively. Correspondence and requests for materials should be addressed to M.-C.H.
Funding
ACKNOWLEDGEMENTS We thank G. Lozano for kindly providing p53–/– MEF and p53–/–, MDM2–/– MEF cells. This work was supported by grants CA 58880, CA 77858 and CA 78633, by a SPORE grant in ovarian cancer (CA 83639) (to M.-C.H.), and by the Nellie Connally Breast Cancer Research Fund at the M. D. Anderson Cancer Center (to M.-C.H.). B.P.Z. and Y.L. are recipients of postdoctoral fellowships from US Department of Defense Breast Cancer Research Training Grant DAMD17-99-1-9264 and US Department of Defense Breast Cancer Research Program (DAMD17-01-0300), respectively. Correspondence and requests for materials should be addressed to M.-C.H.
| Funders | Funder number |
|---|---|
| US Department of Defense Breast Cancer Research Program | DAMD17-99-1-9264 |
| US Department of Defense Breast Cancer Research Program | DAMD17-01-0300 |
| National Childhood Cancer Registry – National Cancer Institute | P50CA083639 |
| University of Texas Anderson Cancer Center |
ASJC Scopus subject areas
- Cell Biology
