Raised expression of the antiapoptotic protein ped|[sol]|pea-15 increases susceptibility to chemically induced skin tumor development

摘要

ped/pea-15 is a cytosolic protein performing a broad antiapoptotic function. We show that, upon DMBA/TPA-induced skin carcinogenesis, transgenic mice overexpressing ped/pea-15 (Tgped/pea-15) display early development of papillomas and a four-fold increase in papilloma number compared to the nontransgenic littermates (Pped/pea-15 mice and only 5% in controls (Pped/pea-15 in both untransformed skin and cultured keratinocytes. ped/pea-15 protein levels were also increased in DMBA/TPA-induced papillomas of both Tgped/pea-15 and control mice. Isolated TPA applications induced Caspase-3 activation and apoptosis in nontransformed mouse epidermal tissues. The induction of both Caspase-3 and apoptosis by TPA were four-fold inhibited in the skin of the Tgped/pea-15 compared to the nontransgenic mice, accompanied by a similarly sized reduction in TPA-induced JNK and p38 stimulation and by constitutive induction of cytoplasmic ERK activity in the transgenics. ped/pea-15 expression was stably increased in cell lines from DMBA/TPA-induced skin papillomas and carcinomas, paralleled by protection from TPA apoptosis. In the A5 spindle carcinoma cell line, antisense inhibition of ped/pea-15 expression simultaneously rescued sensitivity to TPA-induced Caspase-3 function and apoptosis. The antisense also reduced A5 cell ability to grow in semisolid media by 65% (PPped/pea-15 control Caspase-3 function and epidermal cell apoptosis in vivo and determine susceptibility to skin tumor development.