| First Author | Formisano P | Year | 2005 |
| Journal | Oncogene | Volume | 24 |
| Issue | 47 | Pages | 7012-21 |
| PubMed ID | 16044159 | Mgi Jnum | J:102369 |
| Mgi Id | MGI:3607419 | Doi | 10.1038/sj.onc.1208871 |
| Citation | Formisano P, et al. (2005) Raised expression of the antiapoptotic protein ped/pea-15 increases susceptibility to chemically induced skin tumor development. Oncogene 24(47):7012-21 |
| abstractText | 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 (Tg(ped/pea-15)) display early development of papillomas and a four-fold increase in papilloma number compared to the nontransgenic littermates (P<0.001). The malignant conversion frequency was 24% for the Tg(ped/pea-15) mice and only 5% in controls (P<0.01). The isolated application of TPA, but not that of DMBA, was sufficient to reversibly upregulate ped/pea-15 in both untransformed skin and cultured keratinocytes. ped/pea-15 protein levels were also increased in DMBA/TPA-induced papillomas of both Tg(ped/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 Tg(ped/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% (P<0.001) and increased by three-fold tumor latency time (P<0.01). Thus, the expression levels of ped/pea-15 control Caspase-3 function and epidermal cell apoptosis in vivo and determine susceptibility to skin tumor development. |
