The role of protein kinase C and phospholipase D in tumor promotion and apoptosis.
Item
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Title
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The role of protein kinase C and phospholipase D in tumor promotion and apoptosis.
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Identifier
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AAI3047280
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identifier
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3047280
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Creator
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Zhong, Minghao.
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Contributor
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Adviser: David A. Foster
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Date
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2002
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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, Cell
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Abstract
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Human tumorigenesis involves multiple genetic alterations with successive rounds of mutation (initiation) and selected amplification (promotion) of mutated cells. Our laboratory demonstrated previously that the tumor-promoting phorbol ester TPA (12-O-tetradecanoylphorbol-13-acetate) cooperates with c-Src overexpression to transform 3Y1 rat fibroblasts. The 3Y1 cells overexpressing c-Src are therefore capable of detecting tumor-promoting compounds able to cooperate with a signaling oncogene such as an overexpressed tyrosine kinase---a common genetic defect in human cancers---to transform cells.;Because of the likelihood that tamoxifen has tumor-promoting properties beyond its estrogen-mimetic capability, we examined the effect of tamoxifen on the 3Y1c-Src cells. Our study showed that tamoxifen, like TPA, causes the down regulation of protein kinase C delta (PKCdelta) and has tumor promoting effects that cooperate with an overexpressed tyrosine kinase to transform rat fibroblasts.;When 3Y1c-Src cells subjected to serum withdrawal, they undergo apoptosis via a cytochrome c/caspase 9 pathway. If PKC delta was down-regulated, the apoptotic phenotypes induced by serum withdrawal in the 3Y1c-Src cells were suppressed. The apparent survival signal generated by PKC delta down-regulation was independent of the phosphatidylinositol-3-kinase (PI3K)/Akt survival pathway.;3Y1 cells expressing the activated Src kinase (v-Src) are resistant to the apoptotic stimulus of serum withdrawal. v-Src stimulates, whereas c-Src does not stimulate phospholipase D (PLD) activity in 3Y1 cells. These data suggest the possibility that PLD provides a survival signal that overcomes apoptotic signals induced by serum withdrawal. Consistent with this hypothesis, elevated expression of either PLD1 or PLD2 in the 3Y1c-Src cells prevented apoptosis upon serum withdrawal. Moreover, if PLD activity was inhibited in the v-Src-transformed 3Y1 cells, they underwent apoptosis in response to serum withdrawal. Surprisingly, if PLD activity was elevated in the parental 3Y1 cells, these cells became sensitive to the apoptotic stimulus of serum withdrawal. Thus, in the context of tyrosine kinase overexpression, PLD activity provides a survival signal, whereas in the absence of another cell division signal, elevated PLD activity leads to apoptosis.;The data presented in this thesis suggest that the survival signals provided by downregulation of PKC delta or upregulation of PLD may be a critical aspect of tumor progression. Therefore PKC delta and PLD could be targets for therapeutic intervention in cancers.
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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.
