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ToxSci Advance Access published online on June 9, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi220
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received February 14, 2005
Accepted June 2, 2005

Environmental Toxicology

The Role of Protein Kinase C in Regulation of TCDD-Mediated CYP1A1 Gene Expression

Daniel E.W. Machemer 1 and Robert H. Tukey 1*

1 Departments of Pharmacology, Chemistry & Biochemistry, University of California, San Diego, La Jolla, CA 92093-0722

* To whom correspondence should be addressed.
Robert H. Tukey, E-mail: rtukey{at}ucsd.edu


  Abstract

Cytochrome P450 1A1 (CYP1A1) is induced by halogenated and polycyclic aromatic hydrocarbons following activation of the Ah receptor. Protein kinase C (PKC) has been implicated in the regulation of this response. In tissue culture, induction of PKC activity with phorbol esters synergizes the actions of TCDD-induced CYP1A1, while PKC inhibitors block induction of CYP1A1 by TCDD. Here, the actions of specific PKC inhibitors on CYP1A1 induction were examined using a HepG2 human cell line (TV101L) that carries a stably integrated firefly luciferase gene under control of the human CYP1A1 promoter (-1612 / +293). TV101 cells were treated with TCDD and either the kinase inhibitor staurosporine, or one of the PKC inhibitors GF109203X, Gö6983, or Gö6976. Ah receptor-dependent activation of CYP1A1-luciferase and cellular PKC activity were measured. TCDD treatment induced CYP1A1-luciferase activity in an Ah receptor-dependent manner, as determined by binding of nuclear Ah receptor to xenobiotic response elements (XREs). Dose-dependent inhibition of PKC activity by staurosporine was concordant with inhibition of TCDD-induced CYP1A1-luciferase activity. However, PKC inhibitors GF109203X, Gö6983 and Gö6976 blocked PKC activity at concentrations independent of those necessary to block TCDD induction of CYP1A1-luciferase activity. For all inhibitors, reduction in CYP1A1-luciferase activity was independent of Ah receptor activation, as determined by electrophoretic mobility shift analysis of TCDD-activated nuclear Ah receptor. The specific PKC inhibitors did not significantly alter cytosolic or nuclear levels of AhR protein, whether alone or in combination with TCDD. These results suggested that PKC was not the sole factor responsible for regulation of CYP1A1.

Keywords: protein kinase C; cytochrome P450 1A1; regulation; gene expression; signal transduction.
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