Tumorigenic activity and therapeutic inhibition of Rheb GTPase Journal Article

Authors: Mavrakis, K. J.; Zhu, H.; Silva, R. L. A.; Mills, J. R.; Teruya-Feldstein, J.; Lowe, S. W.; Tam, W.; Pelletier, J.; Wendel, H. G.
Article Title: Tumorigenic activity and therapeutic inhibition of Rheb GTPase
Abstract: The AKT-mTOR pathway harbors several known and putative oncogenes and tumor suppressors. In a phenotypic screen for lymphomagenesis, we tested candidate genes acting upstream of and downstream from mTOR in vivo. We find that Rheb, a proximal activator of mTORC1, can produce rapid development of aggressive and drug-resistant lymphomas. Rheb causes mTORC1-dependent effects on apoptosis, senescence, and treatment responses that resemble those of Akt. Moreover, Rheb activity toward mTORC1 requires farnesylation and is readily blocked by a pharmacological inhibitor of farnesyltransferase (FTI). In Pten-deficient tumor cells, inhibition of Rheb by FTI is responsible for the drug's anti-tumor effects, such that a farnesylation-independent mutant of Rheb renders these tumors resistant to FTI therapy. Notably, RHEB is highly expressed in some human lymphomas, resulting in mTORC1 activation and increased sensitivity to rapamycin and FTI. Downstream from mTOR, we examined translation initiation factors that have been implicated in transformation in vitro. Of these, only eIF4E was able to enhance lymphomagenesis in vivo. In summary, the Rheb GTPase is an oncogenic activity upstream of mTORC1 and eIF4E and a direct therapeutic target of farnesyltransferase inhibitors in cancer. © 2008 by Cold Spring Harbor Laboratory Press.
Keywords: signal transduction; protein kinase b; controlled study; protein expression; treatment response; doxorubicin; nonhuman; pyridines; protein function; translation initiation; animal cell; mouse; animals; mice; mice, knockout; animal tissue; cells, cultured; apoptosis; enzyme inhibition; animal experiment; animal model; enzyme activity; phosphorylation; mice, inbred c57bl; transcription factors; cell transformation, neoplastic; blotting, western; reverse transcriptase polymerase chain reaction; rna, messenger; mammalian target of rapamycin; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; proto-oncogene proteins c-akt; pten phosphohydrolase; lymphoma; fibroblasts; tumor suppressor protein p53; translation; immunophenotyping; piperidines; senescence; gene dosage; akt; antibiotics, antineoplastic; proto-oncogene proteins c-myc; initiation factor 4a; drug sensitivity; neuropeptides; cell aging; rapamycin; sirolimus; immunosuppressive agents; eukaryotic initiation factor-4e; mouse model; carcinogenic activity; initiation factor; monomeric gtp-binding proteins; rheb protein; oncogenesis; farnesyltranstransferase
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: 2178
End Page: 2188
Language: English
DOI: 10.1101/gad.1690808
PUBMED: 18708578
PROVIDER: scopus
PMCID: PMC2518821
Notes: --- - "Cited By (since 1996): 39" - "Export Date: 17 November 2011" - "CODEN: GEDEE" - "Source: Scopus"
Citation Impact
MSK Authors
  1. Julie T Feldstein
    297 Feldstein
  2. Ricardo Luis Alves Silva
    3 Silva
  3. Hans Guido Wendel
    98 Wendel
  4. Hong Zhu
    2 Zhu