Abrogating the p53 response: Implications for tumor promotion and drug resistance.
Item
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Title
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Abrogating the p53 response: Implications for tumor promotion and drug resistance.
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Identifier
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AAI3115225
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identifier
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3115225
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Creator
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Abbas, Tarek A.
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Contributor
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Adviser: Jill Bargonetti
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Date
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2004
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Language
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English
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Publisher
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City University of New York.
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Subject
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Biology, Molecular
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Abstract
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The p53 tumor suppressor protein plays a central role in cell cycle regulation and tumor suppression by inducing growth arrest and/or apoptosis. While studies investigating the various aspects of p53 regulation are plentiful, little is known about the regulation of p53 during the course of tumor development. In this study, we investigate signaling to and from the tumor suppressor p53 protein in the context of mitogenic signaling, tumor promotion and the cytotoxic response to the chemotherapeutic agent mitomycin C (MC). We show that the well-defined tumor-promoting phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA) prevents DNA damage-induced p53 up-regulation by a mechanism involving the down-regulation of protein kinase C delta (PKCdelta). We provide evidence that TPA treatment of cells, or inhibition of PKCdelta inhibits the basal transcription from the p53 gene, maintains low p53 mRNA levels in cells with damaged DNA, and blocks p53-dependent apoptosis. Our data provides a mechanistic understanding of tumor promoting activity of the phorbol ester TPA, and suggests that transcriptional regulation of p53 may be a critical determinant of its tumor suppresser functions.;Many chemotherapeutic regimes aim at activating the p53 apoptotic pathway. Mitomycin C (MC), a natural antibiotic and a DNA-alkylating and cross-linking agent, has a cytotoxic chemotherapeutic activity and is known to activate p53. We provide data showing that the various DNA-adducts formed upon treating cells with MC are differentially recognized by the DNA damage sensor p53. We show that there exists a clear correlation between the ability of the various MC-DNA adducts to induce p53 accumulation and their cytotoxic activities. In particular, we show that the DNA-mono-adducts formed upon treating cells with the major intracellular MC metabolite, 2,7-diaminomitosine; 2,7-DAM, are incapable of signaling through p53, and are therefore non-cytotoxic. Our data suggests that the DNA cross-linking activity of MC is required for its ability to signal to p53 and is responsible for its apparent cytotoxicity. Finally, we show that the MC analog and DNA cross-linking agent 10-decarbamoyl-MC (DMC), similar to MC is capable of signaling through p53 and is cytotoxic, but unlike MC is also capable of inducing p53-independent apoptosis.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
