Dephosphorylated C/EBPα Accelerates Cell Proliferation through Sequestering Retinoblastoma Protein

Abstract

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

ACKNOWLEDGMENTS

This work was supported by National Institutes of Health grants AG20752, CA100070, and GM55188 (N.A.T.).

We thank Xiurong She for the assistance with Western blotting experiments.