Dephosphorylated C/EBPalpha accelerates cell proliferation through sequestering retinoblastoma protein.
CCAAT/enhancer-binding protein alpha (C/EBPalpha) has been previously considered a strong inhibitor of cell proliferation which uses multiple pathways to cause growth arrest. In this paper, we describe a new function of C/EBPalpha, which is an acceleration of cell proliferation. This new function of C/EBPalpha is created in proliferating livers by protein phosphatase 2A-mediated dephosphorylation of C/EBPalpha at Ser193. The Ser193-dephosphorylated C/EBPalpha interacts with retinoblastoma protein (Rb) independently on E2Fs and sequesters Rb, leading to a reduction of E2F-Rb repressors and to acceleration of proliferation. This new function of C/EBPalpha requires Rb, since the dephosphorylated C/EBPalpha does not promote proliferation in Rb-negative cells. We also show that a balance of Rb and Ser193-dephosphorylated C/EBPalpha determines if the cells are growth arrested or have an increased rate of proliferation. Consistently with these findings, a significant portion of Rb is sequestered into Rb-C/EBPalpha complexes in proliferating livers, and E2F-Rb complexes are not detectable in these livers. Our data demonstrate a new pathway by which the phosphorylation-dependent switch of biological functions of C/EBPalpha promotes liver proliferation.
Wang
Guo-Li
GL
Department of Pathology and Huffington Center on Aging, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Timchenko
Nikolai A
NA
D041721:3T3-L1 Cells; D000595:Amino Acid Sequence; D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism*; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050704:E2F4 Transcription Factor; D015180:Electrophoresis, Gel, Two-Dimensional; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation; D054648:Protein Phosphatase 2; D016160:Retinoblastoma Protein / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D022763:CCAAT-Enhancer-Binding Protein-alpha; D004268:DNA-Binding Proteins; D050704:E2F4 Transcription Factor; D016160:Retinoblastoma Protein; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; D012694:Serine; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2