PMID- 10082561
OWN - NLM
STAT- MEDLINE
DCOM- 19990420
LR  - 20200311
IS  - 0270-7306 (Print)
IS  - 0270-7306 (Linking)
VI  - 19
IP  - 4
DP  - 1999 Apr
TI  - C/EBPalpha regulates formation of S-phase-specific E2F-p107 complexes in livers
      of newborn mice.
PG  - 2936-45
AB  - We previously showed that the rate of hepatocyte proliferation in livers from
      newborn C/EBPalpha 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/EBPalpha. We have observed that C/EBPalpha 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/EBPalpha 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/EBPalpha 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/EBPalpha-mediated regulation of E2F binding is specific, since the deletion of 
      another C/EBP family member, C/EBPbeta, does not change the pattern of E2F
      binding during prenatal liver development. The addition of bacterially expressed,
      purified His-C/EBPalpha to the E2F binding reaction resulted in the disruption of
      E2F complexes containing p107 in nuclear extracts from C/EBPalpha knockout mouse 
      livers. Ectopic expression of C/EBPalpha in cultured cells also leads to a
      reduction of E2F complexes containing Rb family proteins. Coimmunoprecipitation
      analyses revealed an interaction of C/EBPalpha with p107 but none with cdk2,
      E2F1, or cyclin A. A region of C/EBPalpha 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/EBPalpha brings about a change in E2F complex composition 
      through a protein-protein interaction. The disruption of E2F-p107 complexes
      correlates with C/EBPalpha-mediated growth arrest of hepatocytes in newborn
      animals.
FAU - Timchenko, N A
AU  - Timchenko NA
AD  - Department of Pathology, Baylor College of Medicine, Houston, Texas 77030, USA.
      nikolait@bcm.tmc.edu
FAU - Wilde, M
AU  - Wilde M
FAU - Darlington, G J
AU  - Darlington GJ
LA  - eng
GR  - R01 GM055188/GM/NIGMS NIH HHS/United States
GR  - DK49285/DK/NIDDK NIH HHS/United States
GR  - Z01 AG000766/ImNIH/Intramural NIH HHS/United States
GR  - R01 AG00766-01/AG/NIA NIH HHS/United States
GR  - R01 GM55188-01/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Mol Cell Biol
JT  - Molecular and cellular biology
JID - 8109087
RN  - 0 (Arid4a protein, mouse)
RN  - 0 (CCAAT-Enhancer-Binding Proteins)
RN  - 0 (Carrier Proteins)
RN  - 0 (Cdkn1a protein, mouse)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Cyclin A)
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p21)
RN  - 0 (Cyclins)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (E2F Transcription Factors)
RN  - 0 (E2F1 Transcription Factor)
RN  - 0 (E2f1 protein, mouse)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Rbl1 protein, mouse)
RN  - 0 (Retinoblastoma Protein)
RN  - 0 (Retinoblastoma-Binding Protein 1)
RN  - 0 (Retinoblastoma-Like Protein p107)
RN  - 0 (Transcription Factor DP1)
RN  - 0 (Transcription Factors)
RN  - EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
RN  - EC 2.7.11.22 (CDC2-CDC28 Kinases)
RN  - EC 2.7.11.22 (Cdk2 protein, mouse)
RN  - EC 2.7.11.22 (Cyclin-Dependent Kinase 2)
RN  - EC 2.7.11.22 (Cyclin-Dependent Kinases)
SB  - IM
MH  - Animals
MH  - Animals, Newborn
MH  - CCAAT-Enhancer-Binding Proteins
MH  - *CDC2-CDC28 Kinases
MH  - *Carrier Proteins
MH  - Cell Cycle Proteins/analysis
MH  - Cell Nucleus/metabolism
MH  - Cyclin A/analysis
MH  - Cyclin-Dependent Kinase 2
MH  - Cyclin-Dependent Kinase Inhibitor p21
MH  - Cyclin-Dependent Kinases/analysis
MH  - Cyclins/biosynthesis
MH  - DNA-Binding Proteins/genetics/*metabolism
MH  - E2F Transcription Factors
MH  - E2F1 Transcription Factor
MH  - *Gene Expression Regulation, Developmental
MH  - Liver/*embryology
MH  - Mice
MH  - Mice, Knockout
MH  - Nuclear Proteins/*biosynthesis/genetics/*metabolism
MH  - Protein Binding
MH  - Protein-Serine-Threonine Kinases/analysis
MH  - Retinoblastoma Protein/analysis
MH  - Retinoblastoma-Binding Protein 1
MH  - Retinoblastoma-Like Protein p107
MH  - S Phase/*physiology
MH  - Sequence Homology, Amino Acid
MH  - Subcellular Fractions/metabolism
MH  - Transcription Factor DP1
MH  - Transcription Factors/analysis/*biosynthesis/chemistry
PMC - PMC84088
EDAT- 1999/03/19 00:00
MHDA- 1999/03/19 00:01
CRDT- 1999/03/19 00:00
PHST- 1999/03/19 00:00 [pubmed]
PHST- 1999/03/19 00:01 [medline]
PHST- 1999/03/19 00:00 [entrez]
AID - 10.1128/mcb.19.4.2936 [doi]
PST - ppublish
SO  - Mol Cell Biol. 1999 Apr;19(4):2936-45. doi: 10.1128/mcb.19.4.2936.