Survivin regulates the p53 tumor suppressor gene family.
Survivin regulates cell division and inhibits apoptosis by blocking caspase activation. The tumor suppressor p53 inhibits cell cycle progression and induces apoptosis. Since Survivin overexpression and loss of wild-type p53 expression/function occur in most cancers, we investigated whether Survivin regulates p53. Stable overexpression of Survivin protects BaF3 cells from Adriamycin-induced apoptosis, while dominant-negative (T34A) and antisense (AS) Survivin accelerate apoptosis. In BaF3 cells and transiently transfected MCF7 breast cancer cells, elevation of total and phospho-Ser15-p53 in response to Adriamycin is blocked by Survivin and enhanced by Survivin disruption. Furthermore, in Adriamycin-treated MCF7 cells, ectopic Survivin decreased p53 mRNA and increased mRNA and protein of the p53 homologues DeltaNp63 and TAp73 and mRNA for DeltaNp73, suggesting that Survivin may differentially regulate p53 family transcription. Concomitant with decreasing p53 mRNA, Survivin decreased Mdm2 mRNA. Survivin disruption by T34A or AS Survivin resulted in reduced Mdm2 protein. The caspase inhibitor, Z-VAD-FMK, blocked the decrease in Mdm2 as well as the increase in p53 resulting from Survivin disruption, indicating that Survivin regulates Mdm2 at the post-translational level. Proteosome inhibition confirmed that reduced p53 protein observed in cells overexpressing Survivin is due to enhanced p53 degradation resulting from Survivin-mediated inhibition of Mdm2 cleavage by caspases. In summary, our results identify regulatory interactions between Survivin and p53 at the mRNA and protein levels, and suggest that the p53 homologues DeltaNp63, TAp73 and DeltaNp73 may also be regulated by Survivin.
Wang
Zhanxiang
Z
Department of Microbiology and Immunology and The Walther Oncology Center, Indiana University School of Medicine, 950 West Walnut Street, Indianapolis, IN 46202, USA.
Fukuda
Seiji
S
Pelus
Louis M
LM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D061945:Caspase Inhibitors; D004268:DNA-Binding Proteins / Q000235:genetics; D004317:Doxorubicin / Q000494:pharmacology; D005786:Gene Expression Regulation; D016147:Genes, Tumor Suppressor; D016158:Genes, p53; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000502:physiology*; D009363:Neoplasm Proteins; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000032:analysis; D051736:Proto-Oncogene Proteins c-mdm2; D011817:Rabbits; D000077022:Survivin; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins
C107489:BIRC5 protein, human; D061945:Caspase Inhibitors; D004268:DNA-Binding Proteins; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D000077022:Survivin; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C000606369:delta Np73 protein, human; D004317:Doxorubicin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2