Evidence that mitogen-activated protein kinase phosphatase-1 induction by proteasome inhibitors plays an anti-apoptotic role

Inhibitors of the proteasome, a multicatalytic proteinase com-plex responsible for intracellular proteolysis, activate pro-grammed cell death in part through the c-Jun-N-terminal ki-nase (JNK). Proteasome inhibitors also induce mitogen-activated protein kinase phosphatase-1 (MKP-1), however, which can inactivate JNK, and we therefore considered the hypothesis that MKP-1 induction may be antiapoptotic. Over-expression of MKP-1 in A1N4-myc human mammary epithelial and BT-474 breast carcinoma cells decreased proteasome in-hibitor-mediated apoptosis. On the other hand, BT-474 cells stably expressing an MKP-1 small interfering RNA (siMKP-1) and MKP-1 knockout mouse embryo fibroblasts underwent enhanced apoptosis compared with their respective controls. MKP-1-mediated inhibition of apoptosis was associated wit