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PMID: 9372966 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

CCAAT/enhancer binding protein alpha regulates p21 protein and hepatocyte proliferation in newborn mice.

Molecular and cellular biology ·Vol. 17 ·No. 12 ·1997-12-00 ·Pages 7353-61

Timchenko NA, Harris TE, Wilde M, Bilyeu TA, Burgess-Beusse BL, Finegold MJ, Darlington GJ

Abstract

CCAAT/enhancer binding protein alpha (C/EBP alpha) is expressed at high levels in quiescent hepatocytes and in differentiated adipocytes. In cultured cells, C/EBP alpha inhibits cell proliferation in part via stabilization of the p21 protein. The role of C/EBP alpha in regulating hepatocyte proliferation in vivo is presented herein. In C/EBP alpha knockout newborn mice, p21 protein levels are reduced in the liver, and the fraction of hepatocytes synthesizing DNA is increased. Greater than 30% of the hepatocytes in C/EBP alpha knockout animals continue to proliferate at day 17 of postnatal life when cell division in wild-type littermates is low (3%). p21 protein levels are relatively high in wild-type neonates but undetectable in C/EBP alpha knockout mice. The reduction of p21 protein in the highly proliferating livers that lack C/EBP alpha suggests that p21 is responsible for C/EBP alpha-mediated control of liver proliferation in newborn mice. During rat liver regeneration, the amounts of both C/EBP alpha and p21 proteins are decreased before DNA synthesis (6 to 12 h) and then return to presurgery levels at 48 h. Although C/EBP alpha controls p21 protein levels, p21 mRNA is not influenced by C/EBP alpha in liver. Using coimmunoprecipitation and a mammalian two-hybrid assay system, we have shown the interaction of C/EBP alpha and p21 proteins. Study of p21 stability in liver nuclear extracts showed that C/EBP alpha blocks proteolytic degradation of p21. Our data demonstrate that C/EBP alpha regulates hepatocyte proliferation in newborn mice and that in liver, the level of p21 protein is under posttranscriptional control, consistent with the hypothesis that protein-protein interaction with C/EBP alpha determines p21 levels.

MeSH Terms
Animals Animals, Newborn CCAAT-Enhancer-Binding Proteins Cell Division/genetics,physiology Cyclin-Dependent Kinase Inhibitor p21 Cyclins/genetics,metabolism DNA/biosynthesis DNA-Binding Proteins/genetics,metabolism In Vitro Techniques Liver/cytology,metabolism Liver Regeneration/genetics,physiology Mice Mice, Knockout Nuclear Proteins/genetics,metabolism RNA, Messenger/genetics,metabolism Rats
Chemicals
CCAAT-Enhancer-Binding Proteins Cdkn1a protein, mouse Cdkn1a protein, rat Cyclin-Dependent Kinase Inhibitor p21 Cyclins DNA-Binding Proteins Nuclear Proteins RNA, Messenger DNA
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Timchenko N A
Department of Pathology, Baylor College of Medicine, Houston, Texas 77030, USA.
Harris T E
Wilde M
Bilyeu T A
Burgess-Beusse B L
Finegold M J
Darlington G J
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.17.12.7353
Published
1997-12-00
Pages
7353-61
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC232591
Subset
IM
Grants
NIA NIH HHS · AG 13663 · United States
NIDDK NIH HHS · DK45285 · United States
External Links
PubMed source DOI: 10.1128/MCB.17.12.7353 PMC Full Text View journal details
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