Novel phospholipase D/mTOR survival pathway in human breast cancer cells.
Item
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Title
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Novel phospholipase D/mTOR survival pathway in human breast cancer cells.
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Identifier
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AAI3115233
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identifier
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3115233
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Creator
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Chen, Yuhong.
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Contributor
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Adviser: David A. Foster
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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, Cell | Health Sciences, Oncology
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Abstract
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It was recently reported that phosphatidic acid (PA) generated by phospholipase D (PLD) activates mTOR (mammalian target of rapamycin), a protein kinase that regulates cell cycle progression, cell growth and survival signaling. PA binds to the same domain of mTOR as rapamycin (a specific inhibitor of mTOR). The effect of rapamycin on breast cancer cell proliferation was investigated. Initial studies revealed that MCF-7 cells, with relatively low levels of PLD activity, were sensitive to the growth-arresting effects of rapamycin, whereas MDA-MB-231 cells with 10-fold higher PLD activity comparing to MCF-7 cells, were resistant to rapamycin. Elevating PLD activity in MCF-7 cells led to rapamycin resistance; and inhibition of PLD activity in MDA-MB-231 cells increased rapamycin sensitivity. The conclusion from this study was that the PA generated by PLD was able to compete with rapamycin for binding to mTOR, therefore elevated phospholipase D activity confers resistance to rapamycin in human breast cancer cell lines. These data provided the first evidence linking mTOR with the mitogenic effects of PLD.;In serum free condition, Rapamycin induced apoptosis in MDA-MB-231 cell. MDA-MB-435S cells, which has relative very low levels of PLD activity, was far less sensitive to rapamycin. These cells were however sensitive to LY294002, a compound that blocks phosphatidylinositol (PI)-3 kinase (PI3K), an enzyme generating PIP3. PIP3 recruits and activates Akt. The PI3K/Akt pathway has emerged as a critical survival pathway for many cancers. The MDA-MB-231 cells with an active PLD/mTOR survival pathway were resistant to LY294002, indicating that the PLD/mTOR apparently constitutes an alternative survival signal that is active in MDA-MB-231 cells.;In summary, the evidence provided in this thesis further establishes that there is a critical dependence of PLD survival signaling upon mTOR. The PLD/mTOR pathway represents an alternative survival signaling strategy to the established PI3K/Akt pathway.
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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.
