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J. Biol. Chem., Vol. 280, Issue 6, 4350-4359, February 11, 2005

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ERK Kinase Inhibition Stabilizes the Aryl Hydrocarbon Receptor

IMPLICATIONS FOR TRANSCRIPTIONAL ACTIVATION AND PROTEIN DEGRADATION^*

Shujuan Chen, Theresa Operaña, Jessica Bonzo, Nghia Nguyen, and Robert H. Tukey

From the Laboratory of Environmental Toxicology, Department of Pharmacology, Chemistry & Biochemistry, University of California, San Diego, La Jolla, California 92093

The ultimate carcinogen and metabolite of benzo-[a]pyrene-7,8-dihydrodiol, benzo[a]pyrene-r-7,t-8-dihydrodiol-t-9,10-epoxide (±), stimulates apoptosis, and this process can be blocked by extracellular signal-regulated kinase (Erk) kinase inhibitors. However, we show here that Erk kinase inhibitors were unable to prevent B[a]P-7,8-dihydrodiol-induced apoptosis, leading us to speculate that Erk kinases are linked to regulation of the aryl hydrocarbon (Ah) receptor. Cotreatment of hepa1c1c7 cells with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and Erk kinase inhibitor PD98059, U0126, or SL327 led to enhanced nuclear accumulation of Ah receptor but with a reduced capacity to complement TCDD induction of Cyp1a1. This is explained in part by the ability of Erk kinase inhibitors to alter the steady-state levels of cellular Ah receptor, a result that leads to a dramatic induction in detectable receptor levels. These changes in cellular Ah receptor levels are associated with delayed degradation of the Ah receptor because TCDD-initiated degradation is reversed when cells are co-treated with TCDD and Erk kinase inhibitors. Erk kinase is linked to Ah receptor expression, as demonstrated by reductions in total Ah receptor levels after overexpression of constitutively active MEK1. In addition, Erk kinase activity modulates the transcriptional response because MEK1 overexpression enhances TCDD-initiated transactivation potential of the receptor. Thus, Erk kinase activity facilitates ligand-initiated transcriptional activation while targeting the Ah receptor for degradation. Immunoprecipitation experiments of the Ah receptor indicate that Erk kinase activity is associated with the receptor. It is interesting that the carboxyl region of the Ah receptor is associated with the transactivation region as well as the site for ubiquitination, indicating that Erk kinase-dependent phosphorylation targets the carboxyl region of the receptor.

Received for publication, October 12, 2004 , and in revised form, November 23, 2004.

^* This work was supported by Grant Superfund ES10337 from the United States Public Health Service. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Leichtag Biomedical Research Bldg., La Jolla, CA 92093-0722. Tel.: 858-822-0288; Fax: 858-822-0363; E-mail: rtukey{at}ucsd.edu.

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