Liver tumors escape negative control of proliferation via PI3K/Akt-mediated block of C/EBP alpha growth inhibitory activity.
Liver tumor cells arise from normal hepatocytes that escape negative control of proliferation. The transcription factor C/EBPalpha maintains quiescence of hepatocytes through two pathways: inhibition of cdks and repression of E2F. Nevertheless, liver tumors and cultured hepatoma cell lines proliferate in the presence of C/EBPalpha. In this paper, we present evidence that the activation of the PI3K/Akt pathway in liver tumor cells blocks the growth inhibitory activity of C/EBPalpha through the PP2A-mediated dephosphorylation of C/EBPalpha on Ser 193, leading to a failure of C/EBPalpha to interact with and inhibit cdks and E2F. Mutation of Ser 193 to Ala also abolishes the ability of C/EBPalpha to cause growth arrest because of a lack of interactions with cdk2 and E2F-Rb complexes. These data provide a molecular basis for the development of liver tumors in which the activation of PI3K/Akt pathway neutralizes C/EBPalpha growth inhibitory activity.
Wang
Guo-Li
GL
Huffington Center on Aging and Department of Pathology, and Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX 77030, USA.
Iakova
Polina
P
Wilde
Margie
M
Awad
Samir
S
Timchenko
Nikolai A
NA
D041721:3T3-L1 Cells; D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D002455:Cell Division / Q000502:physiology; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured
D022763:CCAAT-Enhancer-Binding Protein-alpha; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D014157:Transcription Factors; C084011:SMARCA2 protein, human; C499503:Smarca2 protein, mouse; C494918:AKT1 protein, human