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, 14-3-3γ was negatively regulated by p53 through binding to its promoter and inhibiting its transcription. In the present study we investigated both p53 and 14-3-3γ protein levels in human lung cancerous tissues and normal lung tissues. We found 14-3-3γ expression correlated to p53 overexpression in lung cancer tissues. Ecotopic expression of wild-type p53, but not mutant p53 (R175H) suppressed both endogenous and exogenous 14-3-3γ in colon and lung cancer cell lines. Further examination demonstrated that p53 interacted with C-terminal domain of 14-3-3γ and induced 14-3-3γ ubiquitination. MG132, a specific inhibitor of the 26S proteasome, could block the effect of p53 on 14-3-3γ protein levels, suggesting that p53 suppressed 14-3-3γ by stimulating the process of proteasome-mediated degradation of 14-3-3γ. These results indicate that the inhibitory effect of p53 on 14-3-3γ is mediated also by a post-transcriptional mechanism. Loss of p53 function may result in upregulation of 14-3-3γ in lung cancers.
Institute of Oncology, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, P.R. China.
De-Yu
DY
Chen
Institute of Oncology, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, P.R. China.
Dong-Fang
DF
Dai
Institute of Oncology, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, P.R. China.
Ye
Y
Hua
Institute of Oncology, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, P.R. China.
Wen-Qing
WQ
Qi
D048948:14-3-3 Proteins / Q000096:biosynthesis* / Q000235:genetics; D017209:Apoptosis / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007976:Leupeptins / Q000008:administration & dosage; D008168:Lung / Q000378:metabolism*; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D059748:Proteolysis; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D054875:Ubiquitination / Q000235:genetics
D048948:14-3-3 Proteins; D007976:Leupeptins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde