Bax gene disruption alters the epidermal response to ultraviolet irradiation and in vivo induced skin carcinogenesis

Bcl-2 family member proteins are differentially expressed in skin and in no n-melanoma skin cancer (NMSC). To elucidate the contribution of bcl-2 and b ax proteins to epidermal differentiation and skin carcinogenesis, we invest igated keratinocyte proliferation, differentiation and tumourigenesis in bc l-2(-/-) and bax(-/-) 'knock-out' mice. The rate and pattern of proliferati on and spontaneous cell death in the bcl-2(-/-) and bax-/- mice were not di fferent from control mice. The epidermis of bcl-2(-/-) and bax(-/-) express ed sightly higher levels of cytokeratin 1 and loricrin compared to control littermates. The apoptotic response to ultraviolet-induced genotoxic stress was assessed by quantitating TUNEL positive cells. Bax(-/-) keratinocytes showed a significant resistance to UV-induced cell death compared to contro l mice. The lifespan of bcl-2(-/-) mice precluded an assessment: of bcl-2 g ene disruption on in vivo tumourigenesis. A significant increase in tumour incidence was observed in bax(-/-) mice compared to control mice in two-ste p chemical carcinogenesis studies. These findings suggest that bcl-2 and ba x gene products may be important determinants of normal keratinocyte differ entiation and response to genotoxic stress in vivo, and indicate that bax m ay provide a tumour suppressor effect during skin carcinogenesis.