| Mdm2 inhibition induces apoptosis in p53 deficient human colon cancer cells by activating p73- and E2F1-mediated expression of PUMA and Siva-1. | |
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MedLine Citation:
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PMID: 20812030 Owner: NLM Status: In-Data-Review |
Abstract/OtherAbstract:
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Camptothecin (CPT) and Nutlin-3 caused apoptosis by increasing p53 protein and its activation in intestinal epithelial cells (IEC-6). We studied the effectiveness of these inducers on apoptosis in human colon cancer cells (Caco2) lacking p53 expression. CPT failed to activate caspase-3 and cause apoptosis in these cells. The absence of p53 expression, higher basal Bcl-xL and lower Bax proteins prevented CPT-induced apoptosis. However, the Mdm2 antagonist Nutlin-3 induced apoptosis in a dose dependent manner by activating caspases-9 and -3. Nutlin-3 prevented the activation of AKT via PTEN-mediated inhibition of the PI3K pathway. Nutlin-3 increased the phosphorylation of retinoblastoma protein causing E2F1 release leading to induction of Siva-1. Nutlin-3-mediated degradation of Mdm2 caused the accumulation of p73, which induced the expression of p53 up-regulated modulator of apoptosis (PUMA). E2F1 and p73 knockdown decreased the expression of Siva and PUMA, respectively and abolished Nutlin-3-induced caspase-3 activation. Cycloheximide (CHX) inhibited Nutlin-3-induced Siva, Noxa, and PUMA expression and inhibited apoptosis in IEC-6 and Caco2 cells. These results indicate that translation of mRNAs induced by Nutlin-3 is critical for apoptosis. In summary, apoptosis in Caco2 cells lacking functional p53 occurred following the disruption of Mdm2 binding with p73 and Rb leading to the expression of pro-apoptotic proteins, PUMA, Noxa, and Siva-1. |
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Authors:
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Ramesh M Ray; Sujoy Bhattacharya; Leonard R Johnson |
Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Apoptosis : an international journal on programmed cell death Volume: 16 ISSN: 1573-675X ISO Abbreviation: Apoptosis Publication Date: 2011 Jan |
Date Detail:
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Created Date: 2011-01-24 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9712129 Medline TA: Apoptosis Country: United States |
Other Details:
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Languages: eng Pagination: 35-44 Citation Subset: IM |
Affiliation:
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Department of Physiology, University of Tennessee Health Science Center, 894 Union Ave., Nash Building, Memphis, TN, 38163, USA, rray3@uthsc.edu. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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