The role of Inducer Caspases and Bcl-2 in the mitochondrial Apoptotic Response

Induction of apoptosis (programmed cell death) is a central physiologic and therapeutic approach to combat cancer. Cell death is induced by a plethora of signals that appear to converge into a central "cell death executioner", the mitochondrion. The applicant proposes to clarify the potential role of certain caspases (cysteine aspartases, proteases) that, unlike most caspases, act upstream of the mitochondrion and how Bcl-2 family members might affect this pathway. First, he will investigate whether these caspases act directly upon the mitochondrion or require intermediate cytosolic proteins. Second, the (cytosolic or membraneous) molecules that transmit this response shall be purified. The third specific aim will address whether Bcl-2 or Bcl-X L interferes with the inducer caspase- triggered mitochondrial response and whether these molecules themselves might be targets of caspases.