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Molecular and Cellular Biology, February 2005, p. 1325-1338, Vol. 25, No. 4
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.4.1325-1338.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Dephosphorylated C/EBP{alpha} Accelerates Cell Proliferation through Sequestering Retinoblastoma Protein

Guo-Li Wang1 and Nikolai A. Timchenko1*

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

* Corresponding author. Mailing address: Department of Pathology and Huffington Center on Aging, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Phone: (713) 798-1567. Fax: (713) 798-4161. E-mail: nikolait{at}bcm.tmc.edu.

Molecular and Cellular Biology, February 2005, p. 1325-1338, Vol. 25, No. 4
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.4.1325-1338.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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