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J Biol Chem, Vol. 275, Issue 8, 5867-5873, February 25, 2000
From the Although liver is an estrogen target tissue, the
number of hepatic genes known to be directly induced by estrogen is
very small. We identified proteinase inhibitor 9, or PI-9, as being rapidly and strongly induced by estrogen in an estrogen
receptor-positive human liver cell line (HepG2-ER7). Since PI-9
mRNA was also induced by estrogen in a human liver biopsy sample,
PI-9 is a genuine estrogen-regulated human gene. PI-9 is a potent
inhibitor of granzyme B and of granzyme B-mediated apoptosis. Estrogens
induced PI-9 mRNA within 2 h, PI-9 mRNA levels reached a
plateau of 30-40-fold induction in 4 h, and induction was not
blocked by cycloheximide, indicating that induction of PI-9 mRNA is
a primary response. The antiestrogen trans-hydroxytamoxifen
was a partial agonist for PI-9 mRNA induction, whereas the
antiestrogen ICI 182,780 was a pure antagonist. Western blot analysis
showed that estrogen strongly increases PI-9 protein levels. Inhibition
of transcription with actinomycin D resulted in identical rates of PI-9
mRNA decay in the presence and absence of estrogen. We isolated
genomic clones containing the PI-9 promoter region, identified a
putative transcription start site, and carried out transient
transfections of PI-9-luciferase reporter gene constructs. The
estrogen, moxestrol, elicited a robust induction from the
PI-9-luciferase reporter. Mutational inactivation of three potential
imperfect estrogen response elements in the PI-9 5'-flanking region had
no effect on moxestrol estrogen receptor induction.
The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EMBL Data Bank with accession number(s) AF200209.
Proteinase Inhibitor 9, an Inhibitor of Granzyme B-mediated
Apoptosis, Is a Primary Estrogen-inducible Gene in Human Liver
Cells*
§¶,¶,,
,,
Department of Biochemistry, University of
Illinois, Urbana, Illinois 61801, § Department of
Gastroenterology, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo
113-8655, Japan, and ** Department of Cancer Research, Berlex
Biosciences, Richmond, California 94804
*
This research was supported by National Institutes of Health
Grant HD-16720 and by a predoctoral fellowship from the U. S. Army
Medical Research and Material Command Breast Cancer Research Program
(to S. K.).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.
Present Address: Curagen Corp. New Haven, CT 06511.
To whom correspondence should be addressed: Dept. of
Biochemistry, 413 RAL, 600 S. Mathews Ave., Urbana, IL 61801. Tel.:
217-333-1788; Fax: 217-244-5858; E-mail: djshapir@uiuc.edu.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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