The anti-apoptosis protein, survivin, mediates gastric epithelial cell cytoprotection against ethanol-induced injury via activation of the p34cdc2 cyclin-dependent kinase
✍ Scribed by Michael K. Jones; Oscar R. Padilla; Nicole A. Webb; Manith Norng
- Publisher
- John Wiley and Sons
- Year
- 2008
- Tongue
- English
- Weight
- 685 KB
- Volume
- 215
- Category
- Article
- ISSN
- 0021-9541
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✦ Synopsis
Abstract
The anti‐apoptosis protein, survivin, promotes cell survival and mitosis. Recent studies have demonstrated that survivin is expressed in normal gastric mucosa. Using an in vitro model, we examined whether survivin plays a role in the cytoprotection produced in gastric mucosa by mild irritant ethanol (ETOH) against subsequent exposure to concentrated ETOH. Pre‐treatment of rat gastric epithelial cells with 1% ETOH reduced cell death, in response to subsequent incubation with 5% ETOH, by 94% (P < 0.005). This pre‐treatment also resulted in increased total and phosphorylated survivin protein levels by 180% (P < 0.0001) and 540% (P < 0.0002), respectively, which required the p34^cdc2^ cell cycle‐dependent kinase. The cytoprotective effect was abrogated upon siRNA knockdown of survivin protein levels. Further, overexpression of exogenous survivin resulted in significant cytoprotection by 62% (P < 0.02) in the absence of any pre‐treatment. We further examined the in vivo relevance of these findings. In fasted rats, administration of 20% ETOH, which we found to be 93% (P < 0.0001) cytoprotective against 50% ETOH challenge, resulted in increased total and phosphorylated survivin protein levels by 234% (P < 0.001) and 214% (P < 0.02), respectively. Administration of 20% ETOH resulted in increased gastric p34^cdc2^ activity by 146% (P < 0.01). Inhibition of p34^cdc2^ by the potent inhibitor, roscovitine, abolished the increased survivin levels in response to pre‐administration of 20% ETOH and reduced the cytoprotection against 50% ETOH challenge by 59% (P < 0.01). These results indicate that survivin is a key mediator of cytoprotection against ETOH‐induced gastric injury, acting at the epithelial cell level, by a mechanism that is dependent, in part, on p34^cdc2^. J. Cell. Physiol. 215: 750–764, 2008. © 2008 Wiley‐Liss, Inc.