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Vol. 52, Issue 6, 974-982, 1997
Department of Physiology and Pharmacology, College of Veterinary
Medicine, Texas A & M University, College Station, Texas 77843
Previous studies in this laboratory have demonstrated that
transcriptional deregulation of c-Ha-ras expression is associated with
the induction and maintenance of proliferative vascular smooth muscle
cell (SMC) phenotypes by benzo[a]pyrene (BaP). We
examined previously undescribed cis-acting elements
within the proximal 5
regulatory region of c-Ha-ras (
550 to +220)
for their ability to influence BaP-induced transcription in murine
SMCs. BaP-inducible DNA binding activity was demonstrated at a site
located 30 relative to the major start site cluster at +1 that
exhibits extensive homology to a consensus aryl hydrocarbon response
element (AHRE), as well as a site located at 543 that contains a
consensus electrophile response element (EpRE). In
vitro cross-linking studies revealed the specific
interaction of 104- and 96-kDa proteins with the putative AHRE and of
an 80-kDa protein with the EpRE. The use of monoclonal antibodies to
the aryl hydrocarbon receptor transcription factor in competition
electrophoretic mobility shift assays indicated this protein is
specifically induced by BaP to interact at the AHRE within the
c-Ha-ras 5 regulatory region. Transient transfection with
an Ha-ras promoter construct containing the putative AHRE but lacking the EpRE linked to the chloramphenicol acetyl transferase reporter gene, followed by challenge with BaP (0.3, 3.0, and 30 µM), revealed transcriptional activation that was not
statistically significant. However, insertion of an oligonucleotide
composed of the EpRE immediately upstream of basal sequences at 330
was associated with strong activation of transcription by BaP. These data indicate that c-Ha-ras gene expression is modulated by
BaP via a complex mechanism that likely involves interactions among multiple regulatory elements. We conclude that c-Ha-ras expression is
regulated by BaP at the transcriptional level, a response that may
constitute an epigenetic basis of atherogenesis.
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