1153 AHR controls keratinocyte stress responses to UVB radiation: Role of the p27 tumor suppressor protein

Exposure of epidermal keratinocytes to UVB radiation leads the intracellular formation tryptophan photoproducts which subsequently activate aryl hydrocarbon receptor (AHR) induce mal-/adaptive stress responses. Previously, we have found that AHR represses nucleotide excision repair and apoptosis in UVB-irradiated thereby contributes skin photocarcinogenesis mice. The mechanisms by interferes with both defense are not clear but probably involve an enhanced proteolysis tumor suppressor p27. Herein, investigated functional relevance p27 (encoded CDKN1B gene) for AHR-mediated modulation DNA double-strand breaks (DSBs) human keratinocytes. Notably, majority UVB-induced DSBs occurs when damaged cells enter mitosis replication forks collapse at sites photoproducts. Based on our established AHR-knockdown (HaCaT-shAHR) empty vector control (HaCaT-EV) keratinocytes, generated CDKN1B- (HaCaT-shCDKN1B) AHR/CDKN1B-knockdown (HaCaT-shAHR_shCDKN1B) cells. exposure (200 J/m2) HaCaT-EV led a rapid activation checkpoint kinase 1 RAD51, axis critical initiation DSB via homologous recombination. Expression phosphorylation proteins was reduced HaCaT-shAHR HaCaT-shCDKN1B HaCaT-shAHR_shCDKN1B Accordingly, later time points after irradiation, exhibited elevated amount γH2AX (DSB marker), apoptotic as compared These effects were reversed cells, emphasizing important role is playing AHR-regulated part response. In summary, these data identify cell-cycle inhibitor novel regulator damage responses UVB-exposed antagonism or proteasome inhibition may be suitable approaches elevate cutaneous protein level prevent photocarcinogenesis.