RESUMO
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.
Assuntos
Citoplasma/metabolismo , Citoplasma/efeitos da radiação , Receptores de Hidrocarboneto Arílico/metabolismo , Raios Ultravioleta , Transporte Ativo do Núcleo Celular , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Carbazóis/química , Carbazóis/metabolismo , Linhagem Celular , Núcleo Celular/metabolismo , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Receptores ErbB/metabolismo , Regulação da Expressão Gênica , Humanos , Indóis/química , Indóis/metabolismo , Camundongos , Camundongos Knockout , Estrutura Molecular , Proteínas Proto-Oncogênicas pp60(c-src)/metabolismo , Receptores de Hidrocarboneto Arílico/deficiência , Receptores de Hidrocarboneto Arílico/genética , Transdução de Sinais/efeitos da radiação , Transcrição Gênica/genética , Triptofano/metabolismoRESUMO
The Aryl hydrocarbon receptor repressor (AhRR) is a new member of bHLH-PAS proteins which is important in the regulation of cell growth and differentiation. The AhRR shares structural similarities with Aryl hydrocarbon receptor (AhR) and AhR nuclear translocator (ARNT). The AhRR is thought to be involved in transcriptional control of AhR-regulated genes by sequestering ARNT. Most of the knowledge of regulation and function of the AhRR is from studies in cell lines. Here, we report the tissue distribution of AhRR in AhR deficient and wild type C57BL/6 mice. In addition, the inducibility of the AhRR and Cytochrome P450 (CYP) 1A1 in response to benzo(a)pyrene (B(a)P) (10 mg/kg bw i.p.) was investigated. The results show that the AhRR mRNA expression pattern in untreated C57BL/6 mice varies across tissues with high levels in hearts and brains. In other tissues, AhRR mRNA expression was low. In contrast to wild-type animals, the tissue levels in AhR-/- mice were about two to three orders of magnitude lower. Treatment of wild-type animals with B(a)P resulted in an induced AhRR expression in liver, spleen, lung and ovary. No significant induction of AhRR mRNA was found in brain and heart tissues, which have a constitutively high level of AhRR expression. Simultaneous measurements of CYP1A1 and AhRR mRNA expression do not strongly support the view that the AhRR tissue pattern triggers the tissue specific responsiveness of AhR-regulated genes to B(a)P treatment.
