We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Raised expression of the antiapoptotic protein ped/pea-15 increases susceptibility to chemically induced skin tumor development.
- Authors
Formisano, Pietro; Perruolo, Giuseppe; Libertini, Silvana; Santopietro, Stefania; Troncone, Giancarlo; Raciti, Gregory Alexander; Oriente, Francesco; Portella, Giuseppe; Miele, Claudia; Beguinot, Francesco
- Abstract
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 (P<0.001). The malignant conversion frequency was 24% for the Tgped/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 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% (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.Oncogene (2005) 24, 7012–7021. doi:10.1038/sj.onc.1208871; published online 25 July 2005
- Subjects
SKIN cancer; PROTEINS; APOPTOSIS; CELL death; ONCOLOGY; GENETICS
- Publication
Oncogene, 2005, Vol 24, Issue 47, p7012
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1208871