Abstract
PTEN phosphatase acts as a tumor suppressor by negatively regulating the phosphoinositide 3-kinase (PI3K) signaling pathway. It is unclear which downstream components of this pathway are necessary for oncogenic transformation. In this report we show that transformed cells of PTEN(+/-) mice have elevated levels of phosphorylated Akt and activated p70/S6 kinase associated with an increase in proliferation. Pharmacological inactivation of mTOR/RAFT/FRAP reduced neoplastic proliferation, tumor size, and p70/S6 kinase activity, but did not affect the status of Akt. These data suggest that p70/S6K and possibly other targets of mTOR contribute significantly to tumor development and that inhibition of these proteins may be therapeutic for cancer patients with deranged PI3K signaling.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Alleles
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Animals
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Base Sequence
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Cell Transformation, Neoplastic / drug effects
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DNA Primers / genetics
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Female
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Humans
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Mice
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Mice, Knockout
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PTEN Phosphohydrolase
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoric Monoester Hydrolases / deficiency*
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Phosphoric Monoester Hydrolases / genetics
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Protein Kinase Inhibitors*
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Protein Kinases*
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Ribosomal Protein S6 Kinases / metabolism*
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Signal Transduction
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Sirolimus / analogs & derivatives
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Sirolimus / pharmacology
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TOR Serine-Threonine Kinases
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Tumor Suppressor Proteins*
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Uterine Neoplasms / drug therapy
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Uterine Neoplasms / genetics
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Uterine Neoplasms / metabolism
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Uterine Neoplasms / pathology
Substances
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DNA Primers
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Protein Kinase Inhibitors
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Tumor Suppressor Proteins
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temsirolimus
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Protein Kinases
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MTOR protein, human
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mTOR protein, mouse
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Ribosomal Protein S6 Kinases
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TOR Serine-Threonine Kinases
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Phosphoric Monoester Hydrolases
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PTEN Phosphohydrolase
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PTEN protein, human
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Sirolimus