Carcinogenesis, Vol 19, 771-780, Copyright © 1998 by Oxford University Press
MP Piechocki and RN Hines
The mechanisms that underly the regulation of human CYP1A1 have merited
considerable attention because of their association both with toxic
outcomes and the etiology of several cancers. Previous work conducted in
this laboratory has identified a negative regulatory element (NRE) in the
5' region of this gene that appeared to modulate CYP1A1 transcriptional
activity. This NRE is present in two functional copies, a high affinity
21-bp palindrome centered at position -784, and an additional element found
within a GC-rich region between position -728 and -558. In this report, the
regulatory function of the NREs in the context of the CYP1A1 promoter was
evaluated. This was accomplished by substituting mutated elements for the
corresponding wild-type element in a vector that contained human CYP1A1
sequences positions -1140 to +59 directing the transcription of the
chloramphenicol acetyltransferase reporter gene. Expression vectors
containing specific mutations in each or both NREs were characterized. We
show that eliminating the binding of the CYP1A1 repressor protein to one or
both repressor motifs results in a significant 2- to 3-fold increase in the
inducibility of CYP1A1 promoter activity. Although mutation of both sites
appeared to result in an increase in inducibility over that observed with
only one site mutated, the effect was not additive. Such aberrant
transcriptional activity correlates with the highly inducible aryl
hydrocarbon hydroxylase phenotype that is a reported marker for individuals
predisposed to lung cancer. Mutation of the NRE, or more likely, the
cognate repressor protein(s), may provide a genetic basis for this
phenotype.
ARTICLES
Functional characterization of the human CYP1A1 negative regulatory element: modulation of Ah receptor mediated transcriptional activity
Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201-1998, USA.
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