The effect of phospholipase D on TGF -beta signaling in cancer survival.
Item
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Title
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The effect of phospholipase D on TGF -beta signaling in cancer survival.
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Identifier
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AAI3300698
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identifier
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3300698
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Creator
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Gadir, Noga.
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Contributor
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Adviser: David A. Foster
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Date
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2008
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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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MDA-MB-231 human breast cancer cells have a survival signal generated by phospholipase D (PLD) that involves the activation of the mammalian target of rapamycin (mTOR) and mitogenic activated protein kinase (MAPK). In the absence of serum, rapamycin induces apoptosis in MDA-MB-231 human breast cancer cells. However, in the presence of serum, rapamycin induces G1 cell cycle arrest -- indicating that a factor(s) in serum suppresses rapamycin-induced apoptosis. We find that transforming growth factor-beta (TGF-beta) suppresses rapamycin-induced apoptosis in serum-deprived MDA-MB-231 cells in a protein kinase Cdelta (PKCdelta)-dependent manner. Importantly, if TGF-beta signaling or PKCdelta was suppressed, rapamycin induced apoptosis rather than G1 arrest in the presence of serum. If cells were allowed to progress into S-phase, rapamycin induced apoptosis in the presence of serum. We also examined the effect of rapamycin on cancer cell lines harboring genetic defects in TGF-beta signaling, and as expected, rapamycin induced apoptosis in these cells in the presence of either serum or TGF-beta. Thus, in the absence of TGF-beta signaling, rapamycin becomes cytotoxic rather than cytostatic.;MDA-MB-231 breast cancer cells are resistant to the growth arresting effects of TGF-beta. Since mTOR is a target of PLD signals and mTOR suppresses TGF-beta signaling, we investigated whether the elevated PLD activity in MDA-MB-231 cells is critical for the reported suppression of TGF-beta signaling in these cells. Suppression of PLD activity and/or expression resulted in increased activation of Smads and in addition suppressed phosphorylation of Smad2 on sites that are phosphorylated by MAP kinase and negatively regulate TGF-beta signaling. Suppression of PLD also led to a predictable response of known TGF-beta downstream targets like p21Cip1, p27 Kip1and pRb.;The data presented in this work indicate that the suppressed TGF-beta signaling in MDA-MB-231 cells is due to elevated PLD activity and is mediated by mTOR and MAP kinase. These results point out that the survival signals generated by PLD involve the suppression TGF-beta signals and prevention of G1 arrest. Importantly, this study provides evidence indicating that tumors with defective TGF-beta signaling -- common in colon and pancreatic cancers -- will be selectively sensitive to rapamycin or other strategies that target mTOR.
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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.
