p53 suppresses 14-3-3γ by stimulating proteasome-mediated 14-3-3γ protein degradation

14-3-3 proteins are a family of highly conserved polypeptides that interact with a large number of proteins and play a role in a wide variety of cellular processes. 14-3-3 proteins have been demonstrated overexpressed in several cancers and serving as potential oncogenes. In a previous study we showed one isoform of the 14-3-3 family, 14-3-3 gamma was negatively regulated by p53 through binding to its promoter and inhibiting its transcription. In the present study we investigated both p53 and 14-3-3 gamma protein levels in human lung cancerous tissues and normal lung tissues. We found 14-3-3 gamma expression correlated to p53 overexpression in lung cancer tissues. Ecotopic expression of wild-type p53, but not mutant p53 (R17511) suppressed both endogenous and exogenous 14-3-3 gamma in colon and lung cancer cell lines. Further examination demonstrated that p53 interacted with C-terminal domain of 14-3-3 gamma and induced 14-3-3 gamma ubiquitination. MG132, a specific inhibitor of the 26S proteasome, could block the effect of p53 on 14-3-3 gamma protein levels, suggesting that p53 suppressed 14-3-3 gamma by stimulating the process of proteasome-mediated degradation of 14-3-3 gamma. These results indicate that the inhibitory effect of p53 on 14-3-3 gamma is mediated also by a post-transcriptional mechanism. Loss of p53 function may result in upregulation of 14-3-3 gamma in lung cancers.