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J. Biol. Chem., Vol. 275, Issue 35, 27406-27413, September 1, 2000
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From the Departments of § Medicine and Pathology,
Huffington Center on Aging, Baylor College of Medicine,
Houston, Texas 77030
Lipopolysacharide (LPS) induced acute phase
response (APR) in mouse liver leads to elevation of the low molecular
weight CCAAT/Enhancer binding protein (C/EBP)
Translational Induction of Liver-enriched Transcriptional
Inhibitory Protein during Acute Phase Response Leads to
Repression of CCAAT/Enhancer Binding Protein
mRNA*
,
isoform,
liver-enriched transcriptional inhibitory protein (LIP). In this paper,
we investigate the pathway for LIP induction during APR and the role of
LIP in regulation of the C/EBP
promoter. The 5' region of C/EBP
mRNA has been shown to be involved in the regulation of LIP
translation. Our data demonstrate that binding of cytoplasmic proteins
to the 5' region of C/EBP mRNA is altered in response to LPS
administration. One of the major changes is induced binding of a
cytoplasmic protein that is immunologically identical to the previously
characterized RNA-binding protein CUGBP1. Induction of CUGBP1 binding
activity in liver cytoplasm during APR is accompanied by the elevation of CUGBP1 binding activity on polysomes. CUGBP1 immunoprecipitated from
livers of LPS-treated mice, but not from normal animals, is capable of
inducing LIP translation in a cell-free translation system. The ability
of CUGBP1 to induce LIP translation during APR depends on
phosphorylation of CUGBP1. We show that elevation of LIP during APR and
after partial hepatectomy leads to increased binding of LIP to
the C/EBP consensus site found within the mouse C/EBP promoter. This
binding correlates with reduction of C/EBP mRNA levels in both
biological situations. Co-transfection experiments showed that
full-length C/EBP activates the C/EBP promoter, while LIP blocks
this activation. Our data suggest that the dominant negative isoform of
C/EBP, LIP, down-regulates the C/EBP promoter in liver and in
cultured hepatocytes. Because full-length C/EBP and C/EBP
proteins regulate liver proliferation, this function of LIP may be
important in liver growth and differentiation.
*
This work was supported in part by National Institutes of
Health Grants AR10D44387-01 (to L. T. T.), AG00756 (to
N. A. T.), GM55188 (to N. A. T.), and DK53045 (to
G. J. D.), and the Muscular Dystrophy Association (to L. T. T.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Supported by the Training Program in Molecular Endocrinology Grant DK07696.
¶
To whom correspondence should be addressed: Huffington
Center on Aging, N803, Baylor College of Medicine, One Baylor
Plaza, Houston, TX 77030. Tel.: 713-798-1567; Fax: 713-798-4161;
E-mail: nikolait@bcm.tmc.edu.
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