FASEB J. Pierce now sold as Thermo Scientific
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Puga, A.
Right arrow Articles by Nebert, D. W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Puga, A.
Right arrow Articles by Nebert, D. W.

The FASEB Journal, Vol 6, 777-785, Copyright © 1992 by The Federation of American Societies for Experimental Biology

RESEARCH COMMUNICATIONS

Transcriptional derepression of the murine Cyp1a-1 gene by mevinolin

A Puga, B Raychaudhuri and DW Nebert
Laboratory of Developmental Pharmacology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892.

In mouse hepatoma Hepa-1c1c7 cultures, polycyclic aromatic compounds such as benzol[a]pyrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin) activate the Cyp1a-1 (cytochrome P(1)450) and Nmo- 1[NAD(P)H:menadione-oxidoreductase] genes, two members of the aromatic hydrocarbon (Ah)-responsive gene battery. Mevinolin is known to inhibit 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase (EC 1.1.1.34), the rate-limiting step in cholesterol biosynthesis. We show here that in the absence of TCDD, mevinolin markedly increases Cyp1a-1 transcription, CYP1A1 mRNA and protein levels and enzyme activity, and NMO1 mRNA concentrations. Addition of mevalonate, the product of HMG- CoA reductase activity, fails to reverse the effects of mevinolin. In fact, when used at high concentrations, mevalonate activates Cyp1a-1 transcription. Mevinolin-induced Cyp1a-1 gene activation: (1) occurs independently of the lipid content of the growth medium, (2) is not suppressed by adding 25-hydroxycholesterol, which blocks MHG-CoA reductase activity, and (3) requires a functional Ah receptor and unimpaired nuclear translocation of the receptor. It is possible that an unknown metabolite (or metabolites) of mevinolin activates Cyp1a-1 expression and that high concentrations of mevalonate act via the same mechanism. Using chimaeric plasmids that contain different lengths of Cyp1a-1 5' flanking regions fused to the bacterial neomycin (neo) gene, we find that the mevinolin effect on Cyp1a-1 induction requires the 5' flanking sequences between -1647 and -824, which are also needed for TCDD induction. Mevinolin, however, is not a ligand for the Ah receptor. Gel mobility shift assays revealed that Cyp1a-1 activation caused by mevinolin does not involve the ligand-dependent formation of a functional Ah receptor-dependent DNA-binding complex, but instead appears to be correlated with release of a putative repressor from its cognate DNA site. Our results suggest that the basel level of Cyp1a-1 transcription is maintained by an unknown negative regulatory factor. We propose that Cyp1a-1 transcriptional activation can result not only from induction by polycyclic aromatic compounds but also from derepression by mevinolin, independent of HMG-CoA reductase inhibition.


This article has been cited by other articles:


Home page
 J. Biol. Chem.Home page
M. Backlund, I. Johansson, S. Mkrtchian, and M. Ingelman-Sundberg
Signal Transduction-mediated Activation of the Aryl Hydrocarbon Receptor in Rat Hepatoma H4IIE Cells
J. Biol. Chem., December 12, 1997; 272(50): 31755 - 31763.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
M. D. Sadar, R. Ash, J. Sundqvist, P.-E. Olsson, and T. B. Andersson
Phenobarbital Induction of CYP1A1 Gene Expression in a Primary Culture of Rainbow Trout Hepatocytes
J. Biol. Chem., July 26, 1996; 271(30): 17635 - 17643.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Copyright © 1992 by The Federation of American Societies for Experimental Biology.