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Dephosphorylated C/EBP Accelerates Cell Proliferation through Sequestering Retinoblastoma Protein

Huffington Center on Aging and Department of Pathology, Baylor College of Medicine, Houston, Texas¹

Received 19 October 2004/ Accepted 29 November 2004

CCAAT/enhancer-binding protein alpha (C/EBP) 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/EBP, which is an acceleration of cell proliferation. This new function of C/EBP is created in proliferating livers by protein phosphatase 2A-mediated dephosphorylation of C/EBP at Ser193. The Ser193-dephosphorylated C/EBP 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/EBP requires Rb, since the dephosphorylated C/EBP does not promote proliferation in Rb-negative cells. We also show that a balance of Rb and Ser193-dephosphorylated C/EBP 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/EBP 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/EBP promotes liver proliferation.

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