title: Akt deficiency impairs normal cell proliferation and suppresses oncogenesis in a p53-independent and mTORC1-dependent manner.
abstract: Akt contributes to tumorigenesis by inhibiting apoptosis. Here we establish that Akt is required for normal cell proliferation and susceptibility to oncogenesis independently of its antiapoptotic activity. Partial ablation of Akt activity by deleting Akt1 inhibits cell proliferation and oncogenesis. These effects are compounded by deleting both Akt1 and Akt2. In vivo, Akt1 null mice are resistant to MMTV-v-H-Ras-induced tumors and to skin carcinogenesis. Thus, partial ablation of Akt activity is sufficient to suppress tumorigenesis in vitro and in vivo. The effect of Akt deficiency on cell proliferation and oncogenesis is p53 independent but mTORC1 dependent. Surprisingly, upon mTORC1 hyperactivation, the reduction in Akt activity does not impair cell proliferation and susceptibility to oncogenic transformation; thus, Akt may mediate these processes exclusively via mTORC1.
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago, Illinois 60607, USA.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Skeen
authors.forename: Prashanth T
authors.initials: PT
authors.lastname: Bhaskar
authors.forename: Chia-Chen
authors.initials: CC
authors.lastname: Chen
authors.forename: William S
authors.initials: WS
authors.lastname: Chen
authors.forename: Xiao-ding
authors.initials: XD
authors.lastname: Peng
authors.forename: Veronique
authors.initials: V
authors.lastname: Nogueira
authors.forename: Annett
authors.initials: A
authors.lastname: Hahn-Windgassen
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kiyokawa
authors.forename: Nissim
authors.initials: N
authors.lastname: Hay
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D002472:Cell Transformation, Viral; D003433:Crosses, Genetic; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000378:metabolism; D007700:Kinetics; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D046912:Multiprotein Complexes; D009369:Neoplasms / Q000209:etiology* / Q000473:pathology; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt / Q000172:deficiency* / Q000235:genetics; D012190:Retroviridae / Q000235:genetics; D058570:TOR Serine-Threonine Kinases; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D046912:Multiprotein Complexes; D011506:Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D011494:Protein Kinases; C546843:mTOR protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases