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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
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
) 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.
* 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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