C/EBPalpha  Regulates Formation of S-Phase-Specific E2F-p107 Complexes in Livers of Newborn Mice

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Molecular and Cellular Biology, April 1999, p. 2936-2945, Vol. 19, No. 4
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

C/EBP $alpha$ Regulates Formation of S-Phase-Specific E2F-p107 Complexes in Livers of Newborn Mice

Nikolai A. Timchenko,^* Margie Wilde, and Gretchen J. Darlington

Department of Pathology, Baylor College of Medicine, Houston, Texas 77030

Received 24 September 1998/Returned for modification 9 November 1998/Accepted 21 January 1999

We previously showed that the rate of hepatocyte proliferation in livers from newborn C/EBP $alpha$ knockout mice was increased.An examination of cell cycle-related proteins showed that thecyclin-dependent kinase (CDK) inhibitor p21 level was reducedin the knockout animals compared to that in wild-type littermates.Here we show additional cell cycle-associated proteins that areaffected by C/EBP $alpha$ . We have observed that C/EBP $alpha$ controls thecomposition of E2F complexes through interaction with the retinoblastoma(Rb)-like protein, p107, during prenatal liver development. S-phase-specificE2F complexes containing E2F, DP, cdk2, cyclin A, and p107 areobserved in the developing liver. In wild-type animals these complexesdisappear by day 18 of gestation and are no longer present inthe newborn animals. In the C/EBP $alpha$ mutant, the S-phase-specificcomplexes do not diminish and persist to birth. The elevationof levels of the S-phase-specific E2F-p107 complexes in C/EBP $alpha$ knockout mice correlates with the increased expression of severalE2F-dependent genes such as those that encode cyclin A, proliferatingcell nuclear antigen, and p107. The C/EBP $alpha$ -mediated regulationof E2F binding is specific, since the deletion of another C/EBPfamily member, C/EBP $beta$ , does not change the pattern of E2F bindingduring prenatal liver development. The addition of bacteriallyexpressed, purified His-C/EBP $alpha$ to the E2F binding reaction resultedin the disruption of E2F complexes containing p107 in nuclearextracts from C/EBP $alpha$ knockout mouse livers. Ectopic expressionof C/EBP $alpha$ in cultured cells also leads to a reduction of E2F complexescontaining Rb family proteins. Coimmunoprecipitation analysesrevealed an interaction of C/EBP $alpha$ with p107 but none with cdk2,E2F1, or cyclin A. A region of C/EBP $alpha$ that has sequence similarityto E2F is sufficient for the disruption of the E2F-p107 complexes.Despite its role as a DNA binding protein, C/EBP $alpha$ brings abouta change in E2F complex composition through a protein-proteininteraction. The disruption of E2F-p107 complexes correlates withC/EBP $alpha$ -mediated growth arrest of hepatocytes in newbornanimals.

^* Corresponding author. Mailing address: Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, TX77030. Phone: (713) 770-2206. Fax: (713) 770-1032. E-mail: nikolait{at}bcm.tmc.edu.

Molecular and Cellular Biology, April 1999, p. 2936-2945, Vol. 19, No. 4
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

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C/EBP Regulates Formation of S-Phase-Specific E2F-p107 Complexes in Livers of Newborn Mice

C/EBP $alpha$ Regulates Formation of S-Phase-Specific E2F-p107 Complexes in Livers of Newborn Mice