140 GENETICS OF APOPTOSIS
the Bcl-2 family control the mitochondrial pathway, and that permeabilization of the
outer mitochondrial membrane is triggered by the multidomain proteins are also well
established. However, at the molecular level, how the mitochondrial proteins are
released from the intermembrane space is still controversial. The events downstream
of the mitochondria are now well characterized, although the direct effect of the
various substrates degraded by the executioner caspases on the cell-death process still
await to be elucidated. However, the upstream pathways between the initiating
stimuli and activation of the multidomain proteins remain largely unknown. The
mitochondrial pathway can be activated by a wide range of stimuli—how are these
signals detected by the cells and how are they propagated to activate the multidomain
proteins? Are the various multidomain proteins involved in specific apoptotic
signaling pathways activated by specific stimuli, or are they only redundant proteins
with identical function? It would be surprising if the answer to the latter question
proved to be ‘Yes’.
The antiapoptotic protein Bcl-2 is present not only in the mitochondria but also
in other intracellular membranes, the ER, and the nuclear envelope. Could that
indicate that this protein and maybe other Bcl-2 family proteins, in addition to their
involvement in apoptosis, also have other, unrelated functions? The potential channel-
forming activity of the antiapoptotic proteins has, so far, not been attributed any
function in apoptosis, but could this activity be related to some other function?