An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/− mice
Katrina Podsypanina,Richard T. Lee,Chris Politis,Ian Hennessy,Allison Crane,Janusz Puc,Mehran S. Neshat,Hong Wang,Lin Yang,Jay Gibbons,Phil Frost,Valley C. Dreisbach,John Blenis,Zbigniew Gaciong,Peter E. Fisher,Charles L. Sawyers,Lora Hedrick-Ellenson,Ramon Parsons +17 more
TLDR
It is shown that transformed cells of PTEN+/− mice have elevated levels of phosphorylated Akt and activated p70/S6 kinase associated with an increase in proliferation and that inhibition of these proteins may be therapeutic for cancer patients with deranged PI3K signaling.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.read more
Citations
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The phosphatidylinositol 3-Kinase AKT pathway in human cancer.
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References
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Journal ArticleDOI
Negative Regulation of PKB/Akt-Dependent Cell Survival by the Tumor Suppressor PTEN
Vuk Stambolic,Vuk Stambolic,Akira Suzuki,Akira Suzuki,José Luis de la Pompa,José Luis de la Pompa,Christine Mirtsos,Christine Mirtsos,Takehiko Sasaki,Takehiko Sasaki,Jürgen Ruland,Jürgen Ruland,Josef M. Penninger,Josef M. Penninger,David P. Siderovski,David P. Siderovski,Tak W. Mak,Tak W. Mak +17 more
TL;DR: The results show that PTEN may exert its role as a tumor suppressor by negatively regulating the PI3'K/PKB/Akt signaling pathway.
Journal ArticleDOI
New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway
TL;DR: A series of publications over the past year now suggest a mechanism by which PTEN loss of function results in tumors, and PTEN appears to negatively control the phosphoinositide 3-kinase signaling pathway for regulation of cell growth and survival by dephosphorylating the 3 position ofosphoinositides.
Journal ArticleDOI
A mammalian protein targeted by G1-arresting rapamycin–receptor complex
Eric J. Brown,Mark W. Albers,Tae Bum Shin,Kazuo ichikawa,Curtis Keith,William S. Lane,Stuart L. Schreiber +6 more
TL;DR: A mammalian FKBP–rapamycin-associated protein (FRAP) is isolate whose binding to structural variants of rapamycin complexed to FK BP12 correlates with the ability of these ligands to inhibit cell-cycle progression.
Journal ArticleDOI
RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs.
TL;DR: It is proposed that RAFT1 is the direct target of FKBP12-rapamycin and a mammalian homolog of the TOR proteins, which were originally identified by mutations that confer rapamycin resistance in yeast.
Journal ArticleDOI
Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism
Anne-Claude Gingras,Steven P. Gygi,Brian Raught,Roberto D. Polakiewicz,Robert T. Abraham,Merl F. Hoekstra,Ruedi Aebersold,Nahum Sonenberg +7 more
TL;DR: 4E-BP1 phosphorylation by FRAP/mTOR on Thr-37 and Thr-46 is a priming event for subsequent phosphorylated of the carboxy-terminal serum-sensitive sites, including those that interact with eIF4E.