BCL-2 REGULATES THE LEVELS OF THE CYSTEINE PROTEASES ICH AND CPP32 YAMA IN HUMAN NEURONAL PRECURSOR CELLS/

Members of the Bcl-2 family are major regulators of cell death and sur vival. Bcl-2 has been shown to heterodimerize with the death-inducing protein Bar, but: the mechanism of action of Bcl-2 is not fully unders tood. Here we show, using the human NT-2 neuronal cell line, that over expression of Bcl-2 leads to dramatic downregulation of the cysteine p roteases ICH and CPP32/Yama, which are directly involved in cell death . In addition, the nuclear enzyme poly(ADP-ribose) polymerase was clea ved in control cells but not in cells overexpressing Bcl-2 following i nduction of apoptosis. The mRNA levels of ICH and CPP32/Yama were diff erentially affected by Bcl-2 overexpression, suggesting both transcrip tional and post-transcriptional effects of the protein. These results demonstrate novel mechanisms of action of Bcl-2 in influencing the exp ression of death effecters such as the cysteine proteases. The relativ e levels of Bcl-2 and of various cysteine proteases ultimately determi ne survival and death of different cells, including neurons.