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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blotting, Western
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Cell Line, Tumor
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Cell Transformation, Neoplastic / pathology*
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Chromosome Aberrations
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Humans
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Male
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Mechanistic Target of Rapamycin Complex 1
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Mice
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Mice, Transgenic
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Monomeric GTP-Binding Proteins / physiology*
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Multiprotein Complexes
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Neuropeptides / physiology*
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PTEN Phosphohydrolase / physiology*
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Prostatic Intraepithelial Neoplasia / etiology
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Prostatic Intraepithelial Neoplasia / metabolism
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Prostatic Intraepithelial Neoplasia / pathology
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Prostatic Neoplasms / etiology
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Prostatic Neoplasms / metabolism*
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Prostatic Neoplasms / pathology*
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Proteins
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Proto-Oncogene Mas
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Ras Homolog Enriched in Brain Protein
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction
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TOR Serine-Threonine Kinases
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Transcription Factors / physiology*
Substances
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MAS1 protein, human
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Multiprotein Complexes
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Neuropeptides
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Proteins
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Proto-Oncogene Mas
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RHEB protein, human
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RNA, Messenger
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Ras Homolog Enriched in Brain Protein
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Transcription Factors
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Mechanistic Target of Rapamycin Complex 1
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TOR Serine-Threonine Kinases
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PTEN Phosphohydrolase
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Pten protein, mouse
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Monomeric GTP-Binding Proteins