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Transgenic expression of survivin in keratinocytes counteracts UVB-induced apoptosis and cooperates with loss of p53
Douglas Grossman, … , Pier Carlo Marchisio, Dario C. Altieri
Douglas Grossman, … , Pier Carlo Marchisio, Dario C. Altieri
Published October 1, 2001
Citation Information: J Clin Invest. 2001;108(7):991-999. https://doi.org/10.1172/JCI13345.
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Article

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

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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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Figure 1

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Construction and characterization of K14-survivin transgenic mice. (a) T...
Construction and characterization of K14-survivin transgenic mice. (a) The 0.5-kb mouse survivin cDNA, including the stop codon, was cloned into a BamHI site flanked by 2.1 kb of K14 promoter sequences and 2.2 kb of HGH and polyadenylation sequences, and the expression cassette was released from the vector by EcoRI digest. Arrows indicate the approximate location of PCR primers used for genotyping and RT-PCR. (b) RNA isolated from epidermal cells of K14-survivin transgenic (Tg+) and nontransgenic (Tg–) mice was incubated in the presence or absence of reverse transcriptase (RT) and amplified by PCR with primers complementary to K14 and HGH (left) or mouse keratin 2E (right). Molecular-weight (MW) markers are in the far left lanes, and arrows designate predicted products. (c) Lysates (50 μg) prepared from epidermal cells of K14-survivin (Tg+) and nontransgenic (Tg–) mice or aliquots (5 ng) of recombinant survivin (rSurv) were electrophoresed, transferred to nylon membranes, and blotted with Ab’s to survivin or β-actin, as indicated. Molecular-weight markers are shown on the left.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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