Protein tyrosine phosphatase (PTPase) inhibitors induce epithelial apoptosis in rat small intestine: Role of tyrosine phosphorylation of p53 protein

Protein tyrosine phosphorylation is essential for the regulation of cellular metabolism, proliferation, differentiation, and injury. Normal epithelial cells of the small intestine express high level of PTKase and PTPase. Small bowel epithelium renews rapidly, and a few enterocytes in the villus tip undergo spontaneous apoptosis. In the present study, we test our hypothesis that the balance between PTKase and PTPase is involved in the mechanism of apoptosis of intestinal epithelial cells. We found that intraluminal administration of potent PTPase inhibitors, Na₃VO₄ (0.8 mM, 50 ml/kg) and phenylarsine oxide (80 μM, 50 ml/kg), induced epithelial apoptosis in the rat intestine. The process of apoptosis is rapid, occurring within 30 minutes, involving both the villus tips and crypts, and is independent of protein synthesis. A large number of the apoptotic cells were shed into the gut lumen. We showed that several epithelial proteins were tyrosine phosphorylated after PTPase inhibitors, including p53 protein. p53 is constitutively phosphorylated in the epithelia, and its phosphorylation is markedly enhanced during apoptosis after treatment with PTPase inhibitors. We conclude that apoptosis in the intestinal emthelia is governed bv PTPase via tvrosvl nhosohorvlation of p53 protein.