IDENTIFICATION OF THE MDM2 ONCOPROTEIN AS A SUBSTRATE FOR CPP32-LIKE APOPTOTIC PROTEASES

Programmed cell death is mediated by members of the interleukin 1-beta convertase family of proteases, which are activated in response to di verse cell death stimuli. However, the key substrates of these proteas es that are responsible for apoptotic cell death have not been identif ied. Here we report that the MDM2 oncoprotein is cleaved by members of the CPP32 subfamily of interleukin l-p convertase proteases both in v itro and in vivo, resulting in the disappearance of MDM2 from apoptoti c cells. Because MDM2 functions as a negative regulator of the p53 tum or suppressor and because p53 induces apoptosis in response to a varie ty of stimuli, this cleavage of MDM2 by CPP32-like proteases may resul t in deregulation of p53 and contribute directly to the process of apo ptotic cell death.