Survivin is a key factor in the differential susceptibility of gastric endothelial and epithelial cells to alcohol-induced injury.
We previously demonstrated that the anti-apoptosis protein, survivin, plays a protective role against alcohol-induced gastric injury. Since the endothelium is a primary target of alcohol-induced gastric damage, we investigated whether survivin expression is a key factor in the greater susceptibility of gastric endothelial vs. epithelial cells to alcohol-induced injury. Here, we demonstrate that rat gastric epithelial cells (RGM1 cells, an epithelial cell line derived from normal rat gastric mucosa) expressed 7.5-fold greater survivin protein levels vs. rat gastric endothelial cells. Survivin expression correlated with resistance of gastric epithelial vs. endothelial cells to both alcohol-induced cell damage and alcohol-induced apoptosis. Suppression of survivin protein expression levels using siRNA rendered the gastric epithelial cells as susceptible to both alcohol-induced cell damage and apoptosis as the gastric endothelial cells. Conversely, forced overexpression of survivin by transient transfection rendered gastric endothelial cells as resistant to both alcohol-induced cell damage and apoptosis as mock-transfected gastric epithelial cells. Moreover, overexpression of a threonine-34 to glutamate phosphorylation mimic mutant survivin construct rendered gastric endothelial cells significantly more resistant to alcohol-induced damage and apoptosis vs. mock-transfected gastric epithelial cells. These findings indicate that disparate survivin expression levels can explain the discrepancy between gastric epithelial and endothelial cell susceptibility to alcohol-induced injury; and, that a negative charge at amino acid residue 34 on survivin, such as that which naturally occurs by phosphorylation of threonine-34, enhances its property in conferring gastric mucosal protection.
Jones
M K
MK
Research Healthcare Group, VA Long Beach Healthcare System, Long Beach, CA, USA. michael.jones4@med.va.gov
Padilla
O R
OR
Zhu
E
E
D020751:Alcohol-Induced Disorders / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D004198:Disease Susceptibility; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000431:Ethanol / Q000633:toxicity*; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D013272:Stomach Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D000077022:Survivin; D014162:Transfection
C516989:Birc5 protein, rat; D008869:Microtubule-Associated Proteins; D000077022:Survivin; D000431:Ethanol