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.
Regulates Formation of S-Phase-Specific
E2F-p107 Complexes in Livers of Newborn Mice
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
knockout mice was increased. An
examination of cell cycle-related proteins showed that the cyclin-dependent kinase (CDK) inhibitor p21 level was reduced in the
knockout animals compared to that in wild-type littermates. Here we
show additional cell cycle-associated proteins that are affected by
C/EBP
. We have observed that C/EBP
controls the composition of
E2F complexes through interaction with the retinoblastoma (Rb)-like
protein, p107, during prenatal liver development. S-phase-specific E2F
complexes containing E2F, DP, cdk2, cyclin A, and p107 are observed in
the developing liver. In wild-type animals these complexes disappear by
day 18 of gestation and are no longer present in the newborn animals.
In the C/EBP
mutant, the S-phase-specific complexes do not diminish
and persist to birth. The elevation of levels of the S-phase-specific
E2F-p107 complexes in C/EBP
knockout mice correlates with the
increased expression of several E2F-dependent genes such as those that
encode cyclin A, proliferating cell nuclear antigen, and p107. The
C/EBP
-mediated regulation of E2F binding is specific, since the
deletion of another C/EBP family member, C/EBP
, does not change the
pattern of E2F binding during prenatal liver development. The addition
of bacterially expressed, purified His-C/EBP
to the E2F binding
reaction resulted in the disruption of E2F complexes containing p107 in
nuclear extracts from C/EBP
knockout mouse livers. Ectopic
expression of C/EBP
in cultured cells also leads to a reduction of
E2F complexes containing Rb family proteins. Coimmunoprecipitation
analyses revealed an interaction of C/EBP
with p107 but none with
cdk2, E2F1, or cyclin A. A region of C/EBP
that has sequence
similarity to E2F is sufficient for the disruption of the E2F-p107
complexes. Despite its role as a DNA binding protein, C/EBP
brings
about a change in E2F complex composition through a protein-protein interaction. The disruption of E2F-p107 complexes correlates with C/EBP
-mediated growth arrest of hepatocytes in newborn animals.
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