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


Authors: Nardella, C.; Chen, Z.; Salmena, L.; Carracedo, A.; Alimonti, A.; Egia, A.; Carver, B.; Gerald, W.; Cordon-Cardo, C.; Pandolfi, P. P.
Article Title: Aberrant Rheb-mediated mTORC1 activation and Pten haploinsufficiency are cooperative oncogenic events
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 haplo-insufficiency 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. © 2008 by Cold Spring Harbor Laboratory Press.
Keywords: signal transduction; protein kinase b; controlled study; protein expression; human cell; nonhuman; protein function; mouse; phenotype; mammalia; animals; mice; animal tissue; animal experiment; animal model; enzyme activation; cell line, tumor; carcinogenesis; mice, transgenic; transcription factors; cell transformation, neoplastic; prostate cancer; prostatic neoplasms; oncogene; blotting, western; reverse transcriptase polymerase chain reaction; rna, messenger; hyperplasia; mammalian target of rapamycin; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; pten phosphohydrolase; prostatic intraepithelial neoplasia; senescence; negative feedback; chromosome aberrations; neuropeptides; monomeric gtp-binding proteins; rheb; rheb protein; negative feedback loop; prostate tumorigenesis; pten haploinsufficiency
Journal Title: Genes and Development
Volume: 22
Issue: 16
ISSN: 0890-9369
Publisher: Cold Spring Harbor Laboratory Press  
Date Published: 2008-08-15
Start Page: 2172
End Page: 2177
Language: English
DOI: 10.1101/gad.1699608
PUBMED: 18708577
PROVIDER: scopus
PMCID: PMC2518820
DOI/URL:
Notes: --- - "Cited By (since 1996): 29" - "Export Date: 17 November 2011" - "CODEN: GEDEE" - "Source: Scopus"
Altmetric
Citation Impact