Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/80776
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Type: Journal article
Title: Wild-type and mutant p53 mediate cisplatin resistance through interaction and inhibition of active caspase-9
Author: Chee, J.
Saidin, S.
Lane, D.
Leong, S.
Noll, J.
Neilsen, P.
Phua, Y.
Gabra, H.
Lim, T.
Citation: Cell Cycle, 2013; 12(2):278-288
Publisher: Landes Bioscience
Issue Date: 2013
ISSN: 1538-4101
1551-4005
Statement of
Responsibility: 
Jacqueline L.Y. Chee, Suzan Saidin, David P. Lane, Sai Mun Leong, Jacqueline E. Noll, Paul M. Neilsen, Yi Ting Phua, Hani Gabra and Tit Meng Lim
Abstract: The p53 gene has been implicated in many cancers due to its frequent mutations as well as mutations in other genes whose proteins directly affect p53’s functions. In addition, high expression of p53 [wild-type (WT) or mutant] has been found in the cytoplasm of many tumor cells, and studies have associated these observations with more aggressive tumors and poor prognosis. Cytoplasmic mis-localization of p53 subsequently reduced its transcriptional activity and this loss-of-function (LOF) was used to explain the lack of response to chemotherapeutic agents. However, this hypothesis seemed inadequate in explaining the apparent selection for tumor cells with high levels of p53 protein, a phenomenon that suggests a gain-of-function (GOF) of these mis-localized p53 proteins. In this study, we explored whether the direct involvement of p53 in the apoptotic response is via regulation of the caspase pathway in the cytoplasm. We demonstrate that p53, when present at high levels in the cytoplasm, has an inhibitory effect on caspase-9. Concurrently, knockdown of endogenous p53 caused an increase in the activity of caspase-9. p53 was found to interact with the p35 fragment of caspase-9, and this interaction inhibits the caspase-9 activity. In a p53-null background, the high-level expression of both exogenous WT and mutant p53 increased the resistance of these cells to cisplatin, and the data showed a correlation between high p53 expression and caspase-9 inhibition. These results suggest the inhibition of caspase-9 as a potential mechanism in evading apoptosis in tumors with high-level p53 expression that is cytoplasmically localized.
Keywords: p53; gain-of-function; caspase-9; inhibition; cytoplasmic localization; overexpression
Rights: © 2013 Landes Bioscience
RMID: 0020125628
DOI: 10.4161/cc.23054
Appears in Collections:Medicine publications

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