Transgenic expression of survivin in keratinocytes counteracts UVB-induced apoptosis and cooperates with loss of p53
Douglas Grossman, Paul J. Kim, Olivier P. Blanc-Brude, Douglas E. Brash, Simona Tognin, Pier Carlo Marchisio, Dario C. Altieri
Douglas Grossman, Paul J. Kim, Olivier P. Blanc-Brude, Douglas E. Brash, Simona Tognin, Pier Carlo Marchisio, Dario C. Altieri
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Article

Transgenic expression of survivin in keratinocytes counteracts UVB-induced apoptosis and cooperates with loss of p53

Abstract

The inhibitor of apoptosis protein survivin has been implicated in both cell cycle control and apoptosis resistance. To discriminate between these different roles, we used transgenic expression of survivin in the skin as a model for cell proliferation, differentiation, and apoptosis. Transgenic mice expressing survivin under the control of a keratin-14 promoter developed normally, without histologic abnormalities of the skin or hair, epidermal hyperplasia, or developmental abnormalities of basal or suprabasal epidermis. Keratinocyte proliferation assessed under basal conditions, or after ultraviolet-B (UVB) irradiation, or phorbol ester stimulation was unchanged in survivin transgenic mice. In contrast, survivin expression inhibited UVB-induced apoptosis in vitro and in vivo (i.e., sunburn cell formation), whereas it did not affect Fas-induced cell death. When crossed with p53 knockout mice, transgenic expression of survivin in a p53+/– background substituted for the loss of a second p53 allele and further inhibited UVB-induced apoptosis. These data provide the first in vivo evidence that survivin inhibits apoptosis and suggest that this pathway may oppose the elimination of cancerous cells by p53.

Authors

Douglas Grossman, Paul J. Kim, Olivier P. Blanc-Brude, Douglas E. Brash, Simona Tognin, Pier Carlo Marchisio, Dario C. Altieri

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Effect of transgenic survivin on keratinocyte apoptosis in vivo. (a) Sec...
Effect of transgenic survivin on keratinocyte apoptosis in vivo. (a) Sections of UVB-irradiated (600 J/m2) nontransgenic mouse skin were stained with hematoxylin/eosin (left) or for internucleosomal DNA fragmentation by TUNEL (right). Arrows indicate an apoptotic keratinocyte (sunburn cell). (b) Quantitation of UVB-induced apoptosis in vivo. K14-survivin transgenic mice (gray bars) or nontransgenic littermates (white bars) were irradiated with UVB, and 24 hours later exposed skin was excised and sunburn cells were identified and counted by light microscopy and hematoxylin/eosin staining. Data are expressed as number of sunburn cells per linear centimeter of skin analyzed. Error bars indicate SEM of 2 and nine mice per group of unirradiated and irradiated mice, respectively. P value for nontransgenic and K14-survivin mice is noted in parentheses.