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Molecular and Cellular Biology, March 2001, p. 1700-1709, Vol. 21, No. 5
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.5.1700-1709.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Proteasome Inhibition Induces Nuclear Translocation and Transcriptional Activation of the Dioxin Receptor in Mouse Embryo Primary Fibroblasts in the Absence of Xenobiotics

Belen Santiago-Josefat, Eulalia Pozo-Guisado, Sonia Mulero-Navarro, and Pedro M. Fernandez-Salguero*

Departamento de Bioquímica y Biología Molecular y Genética, Facultad de Ciencias, Universidad de Extremadura, 06071 Badajoz, Spain

Received 1 June 2000/Returned for modification 13 July 2000/Accepted 11 November 2000

The aryl hydrocarbon receptor (AHR) is a transcription factor that is highly conserved during evolution and shares important structural features with the Drosophila developmental regulators Sim and Per. Although much is known about the mechanism of AHR activation by xenobiotics, little information is available regarding its activation by endogenous stimuli in the absence of exogenous ligand. In this study, using embryonic primary fibroblasts, we have analyzed the role of proteasome inhibition on AHR transcriptional activation in the absence of xenobiotics. Proteasome inhibition markedly reduced cytosolic AHR without affecting its total cellular content. Cytosolic AHR depletion was the result of receptor translocation into the nuclear compartment, as shown by transient transfection of a green fluorescent protein-tagged AHR and by immunoblot analysis of nuclear extracts. Gel retardation experiments showed that proteasome inhibition induced transcriptionally active AHR-ARNT heterodimers able to bind to a consensus xenobiotic-responsive element. Furthermore, nuclear AHR was transcriptionally active in vivo, as shown by the induction of the endogenous target gene CYP1A2. Synchronized to AHR activation, proteasome inhibition also induced a transient increase in AHR nuclear translocator (ARNT) at the protein and mRNA levels. Since nuclear levels of AHR and ARNT are relevant for AHR transcriptional activation, our data suggest that proteasome inhibition, through a transient increase in ARNT expression, could promote AHR stabilization and accumulation into the nuclear compartment. An elevated content of nuclear AHR could favor AHR-ARNT heterodimers able to bind to xenobiotic-responsive elements and to induce gene transcription in the absence of xenobiotics. Thus, depending on the cellular context, physiologically regulated proteasome activity could participate in the control of endogenous AHR functions.

* Corresponding author. Mailing address: Departamento de Bioquímica y Biología Molecular y Genética Facultad de Ciencias, Universidad de Extremadura, Avda. de Elvas s/n, 06071 Badajoz, Spain. Phone: 34 924 289300, ext. 6867. Fax: 34 924 289419. E-mail: pmfersal{at}unex.es.

Molecular and Cellular Biology, March 2001, p. 1700-1709, Vol. 21, No. 5
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.5.1700-1709.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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