Estrogen-induced activation of mammalian target of rapamycin is mediated via tuberin and the small GTPase Ras homologue enriched in brain.

Estrogen-induced activation of mammalian target of rapamycin is mediated via tuberin and the small GTPase Ras homologue enriched in brain. Research Abstract Details 

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Estrogen-induced activation of mammalian target of rapamycin is mediated via tuberin and the small GTPase Ras homologue enriched in brain. Abstract Text:

Jane Yu,Elizabeth Petri Henske,

Inhibitors of the mammalian target of rapamycin (mTOR) are currently in clinical trials for the treatment of breast cancer. The mechanisms through which mTOR are activated in breast cancer and the relationship of mTOR activation to steroid hormones, such as estrogen, that are known to influence breast cancer pathogenesis, are not yet understood. Using MCF-7 cells as a model, we found that 17-beta estradiol (E(2)) rapidly increased the phosphorylation of downstream targets of mTOR: p70 ribosomal protein S6 kinase, ribosomal protein S6, and eukaryotic initiation factor 4E-binding protein 1. The phosphoinositide-3-kinase inhibitor, wortmannin, and the mTOR inhibitor, rapamycin, blocked E(2)-induced activation of p70 ribosomal protein S6 kinase. We hypothesized that tuberin and the small GTPase Ras homologue enriched in brain (Rheb), regulators of the mTOR pathway, mediate E(2)-induced activation of mTOR. Consistent with this hypothesis, E(2) rapidly (within 5 minutes) stimulated tuberin phosphorylation at T1462, a site at which Akt phosphorylates and inactivates tuberin. E(2) also rapidly decreased the inactive, GDP-bound form of Rheb. Finally, we found that small interfering RNA down-regulation of endogenous Rheb blocked the E(2)-stimulated proliferation of MCF-7 cells, demonstrating that Rheb is a key determinant of E(2)-dependent cell growth. Taken together, these data reveal that the TSC/Rheb/mTOR pathway plays a critical role in the regulation of E(2)-induced proliferation, and highlight Rheb as a novel molecular target for breast cancer therapy.

Estrogen-induced activation of mammalian target of rapamycin is mediated via tuberin and the small GTPase Ras homologue enriched in brain. Publishing Authors By Initials

J Yu,EP Henske,

For similar proteins: neoplasm proteins: tumor suppressor proteins research abstracts see: proteins: neoplasm proteins: tumor suppressor proteins research

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Estrogen-induced activation of mammalian target of rapamycin is mediated via tuberin and the small GTPase Ras homologue enriched in brain. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Cancer research

VOLUME: 66

Page Numbers: 9461-6

Journal Abbreviation: Cancer Res.

ISSN: 1538-7445

DAY: 1

MONTH: Oct

YEAR: 2006

Estrogen-induced activation of mammalian target of rapamycin is mediated via tuberin and the small GTPase Ras homologue enriched in brain. Information

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LANGUAGE: eng

NlmUniqueID: 2984705

Estrogen-induced activation of mammalian target of rapamycin is mediated via tuberin and the small GTPase Ras homologue enriched in brain. Keywords Mesh Terms:

KEYWORDS: Tumor Suppressor Proteins

MESH TERMS: physiology

Chemical & Substance for Abstract: Estrogen-induced activation of mammalian target of rapamycin is mediated via tuberin and the small GTPase Ras homologue enriched in brain. Information

Substance Name: Monomeric GTP-Binding Proteins

Registry Number: EC 3.6.5.2

Grant and Affiliation Information for Estrogen-induced activation of mammalian target of rapamycin is mediated via tuberin and the small GTPase Ras homologue enriched in brain.

AFFILIATION: Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.

Country: United States

AGENCY: United States NHLBI

GRANT: R01 HL 31147

ACRONYM: HL

MEDLINETA: Cancer Res

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