Akt-dependent Skp2 mRNA translation is required for exiting contact inhibition, oncogenesis, and adipogenesis.
The requirement of Akt for cell proliferation and oncogenesis is mammalian target of rapamycin complex 1 (mTORC1) dependent. SV40 large T expression in Akt-deficient cells restores cell proliferation rate, but is insufficient for exiting contact inhibition and oncogene-induced anchorage-independent growth, because of a failure to promote Skp2 mRNA translation. Skp2 mRNA and protein are induced upon exiting contact inhibition, which enables entry into mitosis. While Skp2 mRNA is induced in Akt-deficient cells, it is not translated, preventing entry into mitosis. Restoring Skp2 expression in Akt-deficient cells is sufficient to restore exit from contact inhibition and oncogenesis. Skp2 mRNA translation is dependent on mTORC1 and the eukaryotic translation initiation factor 4E (eIF4E). Thus, the requirement of Akt for exiting contact inhibition is mediated by the induction of Skp2 mRNA translation in eIF4E-dependent mechanism. These results provide a new insight into the role of the Akt/mTORC1/eIF4E axis in tumourigenesis. Akt-dependent Skp2 mRNA translation is also required for mitotic clonal expansion (MCE)--the earliest event in adipogenesis. Skp2 re-expression in Akt-deficient preadipocytes, which are impaired in adipogenesis, is sufficient to restore adipogenesis. These results uncover the mechanism by which Akt mediates adipogenesis.
Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60607, USA.
Veronique
V
Nogueira
Deepa
D
Sundararajan
Jennifer M
JM
Kwan
Xiao-ding
XD
Peng
Neha
N
Sarvepalli
Nahum
N
Sonenberg
Nissim
N
Hay
D050156:Adipogenesis; D000818:Animals; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D003260:Contact Inhibition; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D014176:Protein Biosynthesis; D011506:Proteins / Q000378:metabolism*; D044786:S-Phase Kinase-Associated Proteins / Q000096:biosynthesis*; D058570:TOR Serine-Threonine Kinases
D039561:Eukaryotic Initiation Factor-4E; D046912:Multiprotein Complexes; D011506:Proteins; D044786:S-Phase Kinase-Associated Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D051058:Oncogene Protein v-akt; D058570:TOR Serine-Threonine Kinases