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

C Nardella, Z Chen, L Salmena… - Genes & …, 2008 - genesdev.cshlp.org
C Nardella, Z Chen, L Salmena, A Carracedo, A Alimonti, A Egia, B Carver, W Gerald…
Genes & development, 2008genesdev.cshlp.org
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 …
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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