The Arylhydrocarbon Receptor Sees the Light

Abstract

When cells are exposed to ultraviolet light (UVB) the UV response is initiated. This signaling response has two main pathways. The first occurs in the nucleus where UV irradiation causes the formation of DNA photoproducts. A second, DNA-independent, cytoplasmic signaling pathway activates members of the family of mitogen-activated protein kinases (MAPKs). Activation of MAPKs and the resulting inflammation of the skin are important in the development of skin cancers. Although the identity of the initial signaling molecule of this pathway is unknown, some clues pointed to the involvement of the arylhydrocarbon receptor (AhR). AhR is a cytosolic receptor that mediates the toxic effects of polycyclic aromatic hydrocarbons. Upon binding to such compounds, it dissociates from its chaperones, Hsp90 (heat shock protein 90 kD) and c-src, and translocates to the nucleus, where it activates the transcription of cytochrome P450 (also known as CYP ), resulting in the synthesis of CYP protein, an enzyme important in the breakdown of toxic substances. Exposure of human skin to UVB results in the synthesis of CYP, and in vitro UVB irradiation of human cells increases expression of CYP . Fritsche et al . exposed a human keratinocyte cell line (HaCaT), transfected with a plasmid encoding an AhR-green fluorescent protein (GFP) fusion protein, to UVB radiation and monitored (by fluorescent microscopy) translocation of AhR-GFP to the nucleus. Real-time polymerase chain reaction assays showed that UVB irradiation of HaCaT cells (which have endogenous AhR) resulted in increased transcription of CYP1A1 compared with that in cells that had been treated with either an AhR-specific inhibitor or an AhR-specific siRNA (AhR KO) before UVB irradiation. UVB irradiation causes internalization of epidermal growth factor receptors (EGFRs), and the authors used fluorescence microscopy and Western blotting to show that UVB irradiation of HaCaT cells, but not AhR KO cells, resulted in EGFR internalization and the phosphorylation of MAPKs. The internalization of growth factor receptors has been suggested as a crucial early step in the cytosolic UV response. AhR nuclear translocation and CYP1A1 expression were blocked in cells cultured in media depleted of tryptophan. Tryptophan is converted to the AhR ligand FICZ (6-formylindolo[3,2-b]carbazole) after exposure to UVB, but the authors are the first to show this process occurring in UVB-treated human cells. Both CYP1A1 expression and EGFR internalization were measurable in FICZ-treated HaCaT cells, but not in AhR KO cells. FICZ-mediated internalization of EGFR was blocked by inhibition of c-src activity. Finally, the authors showed that UVB irradiation of wild-type, but not AhR-deficient, mice resulted in the induction of CYP1A1 expression, establishing a role for AhR in mediating the UVB stress response in vivo. E. Fritsche, C. Schäfer, C. Calles, T. Bernsmann, T. Bernshausen, M. Wurm, U. Hübenthal, J. E. Cline, H. Hajimiragha, P. Schroeder, L.-O. Klotz, A. Rannug, P. Fürst, H. Hanenberg, J. Abel, J. Krutmann, Lightening up the UV response by identification of the arylhydrocarbon receptor as a cytoplasmic target for ultraviolet B radiation. Proc. Natl. Acad. Sci. U.S.A. 104 , 8851-8856 (2007). [Abstract] [Full Text]