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Vol. 53, Issue 4, 691-700, April 1998
Graduate Program in Biochemistry Cell and Molecular Biology
(W.P.L.) and
Center for Molecular Toxicology (M.P.-G., J.C.T., G.H.P.),
Department of Veterinary Science, The Pennsylvania State University,
University Park, Pennsylvania 16802
The role of protein kinase C (PKC) in the human aryl hydrocarbon
receptor (hAhR) signal transduction pathway was examined in cell lines
stably transfected with pGUDLUC6.1, in which luc+ is solely
controlled by four dioxin-responsive elements (DREs). These cell lines,
P5A11 and HG40/6, were derived from HeLa and HepG2 cells respectively.
Simultaneous treatment of these cells with
2,3,7,8,-tetrachlorodibenzo-p-dioxin (TCDD) and
phorbol-12-myristate-13-acetate (PMA) enhanced
trans-activation of the reporter construct several-fold relative to cells treated with TCDD alone. PKC inhibitors block the PMA
effect and hAhR-mediated signal transduction, demonstrating these
processes require PKC activity. Examination of other independently generated, HeLa-derived cell lines stably transfected with pGUDLUC6.1 demonstrates the PMA effect in P5A11 cells is not a clonal artifact. Transient transfections indicate the PMA effect is not due to a
luciferase message/gene product stabilization mechanism or stimulation of the basal transcription machinery. Examination of cytosolic preparations demonstrates PKC stimulation or inhibition does not alter
hAhR and hAhR nuclear translocator protein levels or TCDD-induced down-regulation of hAhR levels. Similarly, examination of nuclear extracts indicated PKC stimulation or inhibition does not alter nuclear
AhR levels or hAhR/hAhR nuclear translocator protein heterodimer DRE-binding activity as assessed by electrophoretic mobility shift assay. These results demonstrate a PKC-mediated event is required for
the hAhR to form a functional transcriptional complex that leads to
trans-activation and that the DRE is the minimal DNA element required for PMA to enhance AhR-mediated
trans-activation.
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