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Mismatch Repair Protein-Dependent Cytotoxic Signaling In Cells Treated With The Cancer Chemotherapeutic Cisplatin

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abstract
Mismatch repair (MMR) proteins participate in cytotoxicity induced by specific genotoxic agents, including cisplatin (CDDP, cis-diamminedichloroplatinum(II)), a cancer chemotherapeutic drug utilized clinically to treat a variety of malignancies. The MMR protein complex MutSα (consisting of the MSH2 and MSH6 proteins) binds to CDDP-DNA adducts and initiates MMR protein-dependent cell death in cells treated with CDDP; however, the molecular events underlying this death were previously unclear. MMR proteins have been suggested to be important in clinical responses to CDDP; as such, a clear understanding of the mechanisms of CDDP-induced, MMR protein-dependent cell death is critical. This study demonstrates a CDDP-induced pro-death signaling mechanism which is dependent upon the MMR proteins MSH2 and MSH6. This signaling mechanism employs the tyrosine kinase c-Abl, as well as the pro-death signaling molecules cytochrome c, caspase-9 and caspase-3. CDDP induces unique conformational changes in the yeast MutSα complex, suggesting a possible mechanism for the engagement of pro-death signaling machinery. Furthermore, signaling via the pro-apoptotic p53 and p73 proteins, as well as double-strand break and replicative stress respondents ATM, γH2AX and Chk1 occurs independently of MMR protein status upon treatment of cells with CDDP, suggesting that these proteins are not involved in CDDP-induced, MMR protein-dependent cytotoxic signaling. This study additionally reveals evidence for an MMR protein-dependent S phase arrest in CDDP-treated cells, which is temporally associated with MMR protein-dependent death. Findings presented in this study are the first indication of a required signaling mechanism in CDDP-induced, MMR protein-dependent cytotoxicity. This distinct signaling pathway defines a critical contribution of MMR proteins to the control of cell death. This work has clinical implications in the usage and efficacy of CDDP in cancer treatment.
subject
mismatch repair
cell death
DNA damage
cisplatin
contributor
Topping, Ryan (author)
Ornelles, David (committee chair)
Scarpinato, Karin (committee member)
Akman, Steven (committee member)
Lyles, Douglas (committee member)
Torti, Suzy (committee member)
date
2009-08-07T14:15:36Z (accessioned)
2010-06-18T18:58:14Z (accessioned)
2009-08-07T14:15:36Z (available)
2010-06-18T18:58:14Z (available)
2009-08-07T14:15:36Z (issued)
degree
Cancer Biology (discipline)
identifier
http://hdl.handle.net/10339/14744 (uri)
language
en (iso)
publisher
Wake Forest University
rights
Release the entire work immediately for access worldwide. (accessRights)
title
Mismatch Repair Protein-Dependent Cytotoxic Signaling In Cells Treated With The Cancer Chemotherapeutic Cisplatin
type
Dissertation

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