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J. Biol. Chem., Vol. 276, Issue 29, 27272-27280, July 20, 2001
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From the Activating transcription factor 3 (ATF3) is an early response gene that is induced
rapidly during in vivo situations of cellular growth such
as liver regeneration. However, neither the physiological function nor
the potential target genes of this transcription factor related to
cellular proliferation have been identified in the liver or other
tissues. We demonstrate here that endogenous ATF3 mRNA
expression is rapidly induced up to 4-fold upon mitogenic stimulation
of quiescent Hepa 1-6 mouse hepatoma cells. Overexpression of
exogenous ATF3 results in a significant, dose-dependent
increase in DNA synthesis of up to 140% over control cells.
ATF3-transfected cells also display significantly higher rates of
[3H]thymidine incorporation in comparison with
nontransfected controls in the presence of serum. Northern blot
analysis and co-transfection experiments demonstrate that
overexpression of ATF3 enhances cyclin D1 mRNA expression and
activates the cyclin D1 promoter 2.5-fold when activating protein-1
(AP-1) and cyclic AMP response element (CRE) sites within the
promoter are intact. ATF3-mediated promoter activation is reduced to
1.3-fold and 1.6-fold respectively when the AP-1 or CRE sites are
mutated, and mutation of both sites simultaneously leads to the
complete abrogation of promoter activation. Furthermore, DNA-binding
studies demonstrate that ATF3 binds directly to the AP-1 site within
the cyclin D1 promoter. These results indicate that
ATF3 expression stimulates hepatocellular
proliferation, suggesting that this effect is mediated,
at least in part, by the ATF3-dependent activation of cyclin D1 transcription.
Activating Transcription Factor 3 Induces DNA Synthesis and
Expression of Cyclin D1 in Hepatocytes*
§,
Department of Biomedical Sciences,
University of Guelph, Guelph, Ontario N1G 2W1, Canada and the
¶ Albert Einstein Comprehensive Cancer Center, Division of
Hormone-dependent Tumor Biology, Albert Einstein College of
Medicine, Bronx, New York 10461
*
This work was supported in part by the Canadian Institutes
of Health Research (CIHR) and by Grants R01CA70896, R01CA75503, and
R01CA86072 from the Pfeiffer Foundation (to R. G. P.).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.
A scholar of the Medical Research Council/CIHR. To whom
correspondence should be addressed. Tel.: 519-824-4120, ext. 4935; Fax:
519-767-1450; E-mail: jlamarre@ovcnet.uoguelph.ca.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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