57 research outputs found
Difference in pulmonary permeability between indirect and direct acute respiratory distress syndrome assessed by the transpulmonary thermodilution technique: a prospective, observational, multi-institutional study
Dietary supplements and herbal medicine toxicities—when to anticipate them and how to manage them
Variation in physician recommendations, knowledge and perceived roles regarding provision of end-of-life care
Prise en charge des voies aériennes – 1re partie – Recommandations lorsque des difficultés sont constatées chez le patient inconscient/anesthésié
A national point-prevalence survey of the practice of sedation, analgesia, neuromuscular blockade and delirium assessment in adult intensive care units in Singapore
Critical Care and Shock134122-13
Potential of cross-species microsatellite markers to assess population genetics of the endemic, endangered Nilgiri tahr (Nilgiritragus hylocrius)
Wild-type and mutant p53 mediate cisplatin resistance through interaction and inhibition of active caspase-9
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.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 Li
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