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J. Biol. Chem., Vol. 277, Issue 32, 28411-28417, August 9, 2002
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From the STAT3 is rapidly induced during liver
regeneration in an interleukin 6 (IL-6)-dependent fashion,
and IL-6 is required for normal liver regeneration. We wanted to know
whether STAT3 was also required for liver regeneration but disruption
of the STAT3 gene during embryonic stages causes lethality. Therefore,
an albumin promoter-driven Cre-loxP recombination system was used to
create a STAT3 deletion in the adult mouse liver to study the role of STAT3 in liver regeneration. After partial hepatectomy, there was
virtually no STAT3 RNA or protein induction in Alb+
STAT3fl/fl livers. STAT3 DNA binding activity
was also absent in Alb+ STAT3fl/fl
livers. Unlike in control livers, STAT1 was activated in STAT3 conditional-mutant livers posthepatectomy. Hepatocyte DNA synthesis at
40 h posthepatectomy in Alb+
STAT3fl/fl livers was reduced to approximately
one-third of the control. Alb+
STAT3fl/fl livers had abnormalities in
immediate-early gene activation that largely correlated with but were
not identical to those seen in IL-6
STAT3 Contributes to the Mitogenic Response of Hepatocytes during
Liver Regeneration*
§,§,
**, and
Department of Genetics, University of
Pennsylvania Medical School, Philadelphia, Pennsylvania 19104, the
¶ Center for Neurobiology and Behavior, Columbia University, New
York, New York 10032, the School of Life Sciences, Wellcome
Trust Biocenter, University of Dundee, Dundee DD1 5EH, Scotland,
United Kingdom, and the ** Dipartimento di Genetica, Biologia
e Biochimica, Via Santena 5 bis, 10126 Torino, Italy
/ livers. G1 phase
cyclins including cyclins D1 and E had lower expression levels in
Alb+ STAT3fl/fl livers, indicating
an abnormal G1 to S phase transition. Therefore, STAT3
accounts for part of the DNA synthetic response of the hepatocytes during liver regeneration, which cannot be compensated for by induction
of STAT1. Normal activation of the MAPK pathway in Alb+
STAT3fl/fl livers reinforces the fact that at
least part of the effect of IL-6 on hepatocyte proliferation is not
mediated by STAT3. This study provides the first in vivo
evidence that STAT3 promotes cell cycle progression and cell
proliferation under physiological growth conditions.
*
This work was supported in part by University of
Pennsylvania Digestive and Liver Center Grant P30 DK50306 and National
Institutes of Health Grant DK 58315 (to R. T.) and by MIUR
COFIN (to V. 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.
To whom correspondence should be addressed: Bristol-Myers
Squibb Co., Rt. 141 at Clay Rd., Experimental Station 400, Rm.
2418, Wilmington, DE 19880-0400. Tel.: 302-467-5511; Fax: 302-467-6852; E-mail: rebecca.taub@bms.com.
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