The mammalian target of rapamycin (mTOR) represents a critical signaling crossroad where pathways commonly disrupted in cancer converge. We report here that Rheb GTPase, the upstream activator of the mTOR complex 1 (mTORC1) is amplified in human prostate cancers. We demonstrate that Rheb overexpression promotes hyperplasia and a low-grade neoplastic phenotype in the mouse prostate while eliciting a concomitant senescence response and a negative feedback loop limiting Akt activation. Importantly, we show that Pten haploinsufficiency cooperates with Rheb overexpression to markedly promote prostate tumorigenesis. We conclude that Rheb acts as a proto-oncogene in the appropriate genetic milieu and signaling context.

Aberrant Rheb-mediated mTORC1 activation and Pten haploinsufficiency are cooperative oncogenic events. / C. Nardella;Z. Chen;L. Salmena;A. Carracedo;A. Alimonti;A. Egia;B. Carver;W. Gerald;C. Cordon-Cardo;P. P. Pandolfi. - In: GENES & DEVELOPMENT. - ISSN 0890-9369. - 22(2008), pp. 2172-2177.

Aberrant Rheb-mediated mTORC1 activation and Pten haploinsufficiency are cooperative oncogenic events.

PANDOLFI DE RINALDIS, Pier Paolo
2008

Abstract

The mammalian target of rapamycin (mTOR) represents a critical signaling crossroad where pathways commonly disrupted in cancer converge. We report here that Rheb GTPase, the upstream activator of the mTOR complex 1 (mTORC1) is amplified in human prostate cancers. We demonstrate that Rheb overexpression promotes hyperplasia and a low-grade neoplastic phenotype in the mouse prostate while eliciting a concomitant senescence response and a negative feedback loop limiting Akt activation. Importantly, we show that Pten haploinsufficiency cooperates with Rheb overexpression to markedly promote prostate tumorigenesis. We conclude that Rheb acts as a proto-oncogene in the appropriate genetic milieu and signaling context.
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http://genesdev.cshlp.org/content/22/16/2172.full.pdf+html
Rheb; Pten haploinsufficiency; prostate tumorigenesis; negative feedback loop; senescence
C. Nardella;Z. Chen;L. Salmena;A. Carracedo;A. Alimonti;A. Egia;B. Carver;W. Gerald;C. Cordon-Cardo;P. P. Pandolfi
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/62556
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