p53-Independent Down-Regulation of Mdm2 in Human Cancer Cells Treated with Adriamycin |
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| Institution: | 1. Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA;2. Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA;3. Department of Cell Biology, The Scripps Research Institute, La Jolla, California, USA;4. Department of Surgery, University of California San Diego, San Diego, CA 92103, USA;1. Department of Epidemiology, Harvard T.H. Chan School of Public Health, 677 Huntington Ave, Boston, MA 02115, United States of America;2. Department of Pathology, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215, United States of America;3. Clinical and Translational Epidemiology Unit, Department of Medicine, Massachusetts General Hospital, Bartlett Ext., 9th Floor 55 Fruit St., Boston, MA 02114, United States of America;4. Channing Division of Network Medicine, Department of Medicine, Brigham and Women''s Hospital, 75 Francis St, Boston, MA 02115, United States of America;5. Department of Cancer Epidemiology, Moffitt Cancer Center, 12902 USF Magnolia Drive, Tampa, FL 33612, United States of America;6. Department of Pathology, Stanford University School of Medicine, 300 Pasteur Drive, Lane 235, Stanford, CA 94305-5324, United States of America;7. Department of Pathology, Brigham and Women''s Hospital, 75 Francis St, Boston, MA 02115, United States of America;8. Department of Anatomic & Clinical Pathology, Maine Medical Center, Tufts University School of Medicine, 22 Bramhall Street, Portland, ME 04102-3175, United States of America |
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| Abstract: | Mdm2 is a nuclear phosphoprotein which functions as a negative feedback regulator of the p53 tumor suppressor gene. In this study, we investigated the alteration of Mdm2 and p53 in three human cancer cell lines containing either a wild-type or mutant p53 gene after treatment with Adriamycin (doxorubicin, ADR), a DNA damaging agent. We found that human breast cancer MCF-7 cells containing wild-type p53 were much more susceptible to ADR compared to human breast cancer MDA-MB-231 and human prostate cancer Du-145 cells which contain mutant p53. ADR resulted in a significant dose-dependent accumulation of p53 protein in MCF-7 cells, whereas little or no influence was observed on p53 protein of the two mutant p53 cell lines. However, a significant down-regulation of Mdm2 at protein and mRNA levels was observed in these three cell lines following ADR treatment. Moreover, the decrease of Mdm2 was in both a dose- and time-dependent manner. It is interestingly noted that 5 μM is a critical dose for significant down-regulation of the Mdm2 protein. Selected proteasome inhibitors did not rescue the ADR-caused decline in the expression of Mdm2 protein. Therefore, our present results reveal that ADR can induce a down-regulation of Mdm2 via a p53-independent pathway in human cancer cells and the ubiquitin-proteasome degradation mechanism may not be involved in the decreased expression of Mdm2 protein. |
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