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PNAS 104 (21): 8851-8856

Copyright © 2007 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / CELL BIOLOGY

Lightening up the UV response by identification of the arylhydrocarbon receptor as a cytoplasmatic target for ultraviolet B radiation

Ellen Fritsche*, Claudia Schäfer*, Christian Calles*, Thorsten Bernsmann{dagger}, Thorsten Bernshausen*, Melanie Wurm{ddagger}, Ulrike Hübenthal*, Jason E. Cline*, Hossein Hajimiragha*, Peter Schroeder*, Lars-Oliver Klotz§, Agneta Rannug, Peter Fürst{dagger}, Helmut Hanenberg{ddagger}, Josef Abel*, and Jean Krutmann*,||

*Institut für Umweltmedizinische Forschung (IUF), Auf'm Hennekamp 50, 40225 Düsseldorf, Germany; {dagger}Chemical and Veterinary Control Laboratory, Josef-König-Strasse 40, 48147 Münster, Germany; {ddagger}Department of Pediatric Oncology, Hematology, and Immunology, Children's Hospital, Heinrich Heine University Medical Center, Moorenstrasse 5, 40225 Düsseldorf, Germany; Institute of Environmental Medicine, Karolinska Institutet, Box 210, S-171 77 Stockholm, Sweden; and §Institute for Biochemistry und Molecular Biology I, Heinrich Heine University, Universitätsstrasse 1, 40225 Düsseldorf, Germany

Communicated by Richard B. Setlow, Brookhaven National Laboratory, Upton, NY, March 19, 2007

Received for publication November 9, 2006.

Abstract: UVB radiation-induced signaling in mammalian cells involves two major pathways: one that is initiated through the generation of DNA photoproducts in the nucleus and a second one that occurs independently of DNA damage and is characterized by cell surface receptor activation. The chromophore for the latter one has been unknown. Here, we report that the UVB response involves tryptophan as a chromophore. We show that through the intracellular generation of photoproducts, such as the arylhydrocarbon receptor (AhR) ligand 6-formylindolo[3,2-b]carbazole, signaling events are initiated, which are transferred to the nucleus and the cell membrane via activation of the cytoplasmatic AhR. Specifically, AhR activation by UVB leads to (i) transcriptional induction of cytochrome P450 1A1 and (ii) EGF receptor internalization with activation of the EGF receptor downstream target ERK1/2 and subsequent induction of cyclooxygenase-2. The role of the AhR in the UVB stress response was confirmed in vivo by studies employing AhR KO mice.

Key Words: EGF receptor • 6-formylindolo[3,2-b]carbazole • src • UVB • cyclooxygenase-2


Author contributions: J.A. and J.K. contributed equally to this work; E.F., A.R., P.F., J.A., and J.K. designed research; E.F., C.S., C.C., T. Bernsmann, T. Bernshausen, M.W., U.H., J.E.C., H. Hajimiragha, and P.S. performed research; L.-O.K. and H. Hanenberg contributed new reagents/analytic tools; E.F., T. Bernsmann, and P.F. analyzed data; and E.F., A.R., J.A., and J.K. wrote the paper.

The authors declare no conflict of interest.

This article contains supporting information online at www.pnas.org/cgi/content/full/0701764104/DC1.

||To whom correspondence should be addressed. E-mail: krutmann{at}rz.uni-duesseldorf.de

© 2007 by The National Academy of Sciences of the USA


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