Document Detail

Proteinase inhibitor 9, an inhibitor of granzyme B-mediated apoptosis, is a primary estrogen-inducible gene in human liver cells.
MedLine Citation:
PMID:  10681578     Owner:  NLM     Status:  MEDLINE    
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.
H Kanamori; S Krieg; C Mao; V A Di Pippo; S Wang; D A Zajchowski; D J Shapiro
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  275     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2000 Feb 
Date Detail:
Created Date:  2000-03-30     Completed Date:  2000-03-30     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  5867-73     Citation Subset:  IM    
Department of Biochemistry, University of Illinois, Urbana, Illinois 61801, USA.
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MeSH Terms
Apoptosis / drug effects*
Base Sequence
Blotting, Northern
Carcinoma, Hepatocellular / metabolism
Dose-Response Relationship, Drug
Estrogen Antagonists / pharmacology
Estrogens / pharmacology*
Ethinyl Estradiol / analogs & derivatives,  pharmacology
Gene Expression Regulation
Liver / metabolism
Molecular Sequence Data
Promoter Regions, Genetic
RNA, Messenger / drug effects
Response Elements
Reverse Transcriptase Polymerase Chain Reaction
Serine Endopeptidases / metabolism*
Serine Proteinase Inhibitors / genetics,  physiology
Serpins / genetics,  physiology*
Time Factors
Transcription, Genetic / drug effects
Tumor Cells, Cultured
Grant Support
Reg. No./Substance:
0/Estrogen Antagonists; 0/Estrogens; 0/RNA, Messenger; 0/SERPINB9 protein, human; 0/Serine Proteinase Inhibitors; 0/Serpins; 34816-55-2/moxestrol; 57-63-6/Ethinyl Estradiol; EC 3.4.21.-/GZMB protein, human; EC 3.4.21.-/Granzymes; EC 3.4.21.-/Serine Endopeptidases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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