Transgenic expression of survivin in keratinocytes counteracts UVB-induced apoptosis and cooperates with loss of p53.
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.
Grossman
D
D
Department of Dermatology, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Connecticut 06536, USA.
Kim
P J
PJ
Blanc-Brude
O P
OP
Brash
D E
DE
Tognin
S
S
Marchisio
P C
PC
Altieri
D C
DC
D000818:Animals; D017209:Apoptosis; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D053547:Keratin-14; D015603:Keratinocytes / Q000166:cytology*; D007633:Keratins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D010641:Phenotype; D011401:Promoter Regions, Genetic; D012867:Skin / Q000166:cytology / Q000378:metabolism; D000077022:Survivin; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D014466:Ultraviolet Rays
C107489:BIRC5 protein, human; D002868:Chromosomal Proteins, Non-Histone; D051034:Inhibitor of Apoptosis Proteins; C507540:KRT14 protein, human; D053547:Keratin-14; C507446:Krt14 protein, mouse; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; D016159:Tumor Suppressor Protein p53; D007633:Keratins