Inhibition of tyrosine phosphatases induces apoptosis independent from theCD95 system

The inhibition of protein tyrosine phosphatases by pervanadate, a potent ac tivator of B- and T-cells through the induction of tyrosine phosphorylation and downstream signaling events in different activation cascades, efficien tly induced apoptosis in lymphoid cell lines. Pervanadate elicited apoptosi s could be blocked by the tyrosine kinase inhibitor herbimycin A, This apop totic process involved the activation of caspases 3, 8 and 9, the induction of mitochondrial permeability transition, the release of cytochrome C and the fragmentation of chromosomal DNA, T-cells lacking the CD95 receptor or caspase-8 and T-cells stably overexpressing a transdominant negative form o f the adaptor protein FADD were still susceptible to pervanadate-induced ap optosis, excluding the involvement of the CD95 system or other FADD-depende nt death receptors. The apoptotic program initiated by the inhibition of ty rosine phosphatases did not require the presence of the tyrosine kinase p56 (lck) or phosphatase CD45, whereas Bcl-2 overexpression protected T-cells f rom pervanadate-induced cytochrome C release, caspase-8 cleavage and apopto sis.