Akt deficiency impairs normal cell proliferation and suppresses oncogenesis in a p53-independent and mTORC1-dependent manner.
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.
Skeen
Jennifer E
JE
Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago, Illinois 60607, USA.
Bhaskar
Prashanth T
PT
Chen
Chia-Chen
CC
Chen
William S
WS
Peng
Xiao-ding
XD
Nogueira
Veronique
V
Hahn-Windgassen
Annett
A
Kiyokawa
Hiroaki
H
Hay
Nissim
N
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
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