Essential role of active nuclear transport in apoptosis.
Apoptosis is defined by chromatin condensation, nuclear fragmentation and the formation of apoptotic bodies. Because apoptotic signals are transmitted through a common pathway that includes the target steps of death-driving ICE-family proteases and anti-cell death protein Bcl-2 in the cytoplasm, the signals must be transferred from the cytoplasm to the nucleus, at least to induce the apoptotic manifestation of the nucleus. Small signal molecules might diffuse across nuclear pores, but larger molecules are transported by active mechanisms requiring ATP and GTP hydrolysis. It is not known whether apoptotic signals are transmitted into the nucleus by the mechanisms of active nuclear transport. To test the possibility that active nuclear transport is involved in apoptotic signal transmission, we have analysed the effects of molecules that inhibit active nuclear transport on apoptosis. Wheat germ agglutinin (WGA), excess amounts of p10 protein, Ran-GTPgammaS complex, and anti-PTAC58 antibody, which all inhibit active nuclear transport when exogenously microinjected, prevent Fas-induced apoptotic nuclear manifestation. WGA also prevents apoptotic nuclear change promoted by microinjected active CPP32beta/Yama protease (an ICE family member), which plays an essential role in most apoptosis. The results presented here strongly suggest that active nuclear transport is essential for apoptotic signal transduction.