B-cell lymphoma-2 protein family, apoptosis and the endoplasmic reticulum

The Bcl-2 oncogene encodes a protein that inhibits apoptosis or programmed cell death. Apoptosis is a process critical for development and tissue homeostasis and is of great importance to cancer chemotherapy. The molecular mechanisms of apoptosis are still poorly understood, but it is known that a number of events occur on mitochondria such as membrane permeabilization and release of intermembrane space proteins into the cytoplasm. These mitochondrial events are regulated by the Bcl-2 family of proteins. This family is made up of an anti-apoptotic subfamily (Bcl-2, Bcl-xL, Mcl-1) and two pro-apoptotic subfamilies, the multidomain pro-apoptotic proteins (Bax, Bak, Bok) and the BH3-only subfamily (Bid, Bim, Bik, Bad). These proteins were initially thought to function on the mitochondria to regulate mitochondrial events of cell death, but it has subsequently been shown that Bcl-2 family members can regulate cell death when localized to the endoplasmic reticulum (ER). The work presented here shows that Bcl-2 localized to the ER can inhibit the activation of mitochondria-localized Bax, indicating that an intermediate must exist between the ER and mitochondria. This work also shows that Bcl-2 localized to the ER can bind to BH3-only proteins preventing them from activating Bax on the mitochondria. In addition to anti-apoptotic proteins, it was determined that the pro-apoptotic cleavage fragment of Bcl-2, ΔBH4 could induce apoptosis when localized to the ER, but with less potency than ΔBH4 localized to both the mitochondria and the ER. This work also demonstrates that ΔBH4 and ΔBH4 on the ER can induce the depletion of ER calcium, suggesting a probable mechanism for their toxicity. These data, taken together suggest a model whereby the Bcl-2 family works to regulate ER to mitochondrial communication during apoptosis.