DEATH SUBSTRATES CAME ALIVE

Interleukin 1 beta-converting enzyme (ICE)-like proteases (caspases) p lay an important role in programmed cell death (apoptosis), and elucid ating the consequences of their proteolytic activity is central to our understanding of the molecular mechanisms of cell death. Diverse stru ctural and regulatory proteins and enzymes, including protein kinase C delta, the retinoblastoma protein (a protein involved in cell surviva l), the DNA repair enzyme DNA-dependent protein kinase and the nuclear lamins, undergo specific and limited endoproteolytic cleavage by vari ous caspases during apoptosis. Since individual caspases can cleave mu ltiple substrates, the consequences of cleavage of only a single subst rate are stilt poorly understood. Nevertheless, proteolytic activation of protein kinase C delta may be an important early step in the cell death pathway, and cleavage of the retinoblastoma protein could suppre ss its cell survival function, whereas proteolytic inactivation of DNA repair enzymes might compromise the ability of the cell to reverse DN A fragmentation. On the other hand, cleavages of nuclear and cytoplasm ic structural proteins (e.g. the lamins and Gas2) appear to be require d for or contribute lo the dramatic rearrangements in cellular archite cture that are necessary for the completion of the cell death process. An emerging theme is that parallel and sequential proteolytic activat ion and inactivation of key protein substrates occurs during the multi ple steps of apoptosis.