Transgenic expression of survivin in keratinocytes counteracts UVB-induced apoptosis and cooperates with loss of p53
Transgenic expression of survivin in keratinocytes counteracts UVB-induced apoptosis and cooperates with loss of p53
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DOI：
10.1172/jci13345
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发表时间：
2001-10-01
影响因子：
15.9
通讯作者：
Altieri, DC
中科院分区：
文献类型：
--
作者：
Grossman, D;Kim, PJ;Altieri, DC
凋亡抑制蛋白Survivin参与细胞周期调控和凋亡抵抗。为了区分这些不同的作用，我们使用皮肤中存活素的转基因表达作为细胞增殖、分化和凋亡的模型。在角蛋白-14启动子的控制下表达生存素的转基因小鼠发育正常，没有皮肤或毛发的组织学异常、表皮增生或基底或基底上表皮的发育异常。角质形成细胞增殖评估基础条件下，或紫外线B（UVB）照射后，或佛波酯刺激生存素转基因小鼠不变。相反，存活素表达在体外和体内抑制UVB诱导的细胞凋亡（即，晒伤细胞形成），而它不影响Fas诱导的细胞死亡。当与p53基因敲除小鼠杂交时，在p53（+/-）背景下生存素的转基因表达取代了第二个p53等位基因的缺失，并进一步抑制UVB诱导的细胞凋亡。这些数据提供了第一个在体内的证据，生存素抑制细胞凋亡，并表明，这一途径可能会反对消除癌细胞的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. Keradnocyte 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.