MOMP, cell suicide as a BCL-2 family business

Abstract

Apoptosis shapes development and differentiation, has a key role in tissue homeostasis, and is deregulated in cancer. In most cases, successful apoptosis is triggered by mitochondrial outer membrane permeabilization (MOMP), which defines the mitochondrial or intrinsic pathway and ultimately leads to caspase activation and protein substrate cleavage. The mitochondrial apoptotic pathway centered on MOMP is controlled by an intricate network of events that determine the balance of the cell fate choice between survival and death. Here we will review how MOMP proceeds and how the main effectors cytochrome c, a heme protein that has a crucial role in respiration, and second mitochondria-derived activator of caspase (SMAC), as well as other intermembrane space proteins, orchestrate caspase activation. Moreover, we discuss recent insights on the interplay of the upstream coordinators and initiators of MOMP, the BCL-2 family. This review highlights how our increasing knowledge on the regulation of critical checkpoints of apoptosis integrates with understanding of cancer development and has begun to translate into therapeutic clinical benefit.

Bcl-2 on the brink of breakthroughs in cancer treatment

“…1,2 In this issue of Cell Death and Differentiation, several of the world's leaders in research on Bcl-2 family proteins provide complementary reviews covering multiple facets of this intriguing class of proteins, ranging from cellular and molecular mechanistic insights about how these proteins work and addressing their roles in evolution of programmed cell death mechanisms, mammalian development, cancer genetics, cancer biology and applications towards novel cancer therapies. [3][4][5][6][7][8][9] With the recent approval by FDA of the orally bioavailable and highly selective Bcl-2 inhibitor, venetoclax, for some subtypes of chronic lymphocytic leukemia (CLL), Bcl-2 family proteins are now validated as promising drug targets, with the potential to provide significant advances in the standard of care for patients suffering from oncological maladies and possibly for certain non-oncological diseases as well.…”

“…[4][5][6][7][8][9] The canonical view, shared largely by the authors, envisions that Bax and Bak (proapoptotic proteins that share overall sequence and structural similarity to Bcl-2) oligomerize in the mitochondrial outermembrane to form chains whose ends eventually connect to create lipidic pores that release apoptogenic proteins into the cytosol (cytochrome c, SMAC, Htra2, etc. ), thereby triggering a downstream cascade of cell death protease (caspase) activity.…”

“…Structural and biophysical information about Bcl-2 family proteins in solution and in membranes is reviewed by Andrews and co-workers, 5 highlighting several of the unresolved questions. Green and Kalkavan 6 also cover the question of diversity of mechanisms for promoting Bax/Bak oligomerization in mitochondrial membranes, referencing their work on lipid mediators derived from the sphingomyelin pathway -in addition to the welldefined role for BH3-containing agonists of Bax/Bak (such as Bid and Bim) that operate apparently through a hit-and-run mechanism to trigger Bax and Bak oligomerization in membranes.…”

“…Green and Kalkavan also described the role of Bok, 6 a protein with sequence and structural similarity to Bax and Bak, that appears to constitutively oligomerize in mitochondrial membranes if allowed to accumulate to sufficient levels, which has been documented to occur in the context of overwhelming accumulation of unfolded proteins that exhaust the capacity of the ERAD pathway. Interestingly, anti-apoptotic Bcl-2 family proteins appear to be incapable of interfering with Bok, suggesting perhaps opportunities to bypass Bcl-2-mediated blockade of apoptosis in cancers or to restore apoptosis in cancers that have impaired expression or activity of Bax and Bak -which is well documented in human malignancies.…”

Experimental Characterization of the Binding Affinities between Proapoptotic BH3 Peptides and Antiapoptotic Bcl‐2 Proteins

“…[1] Nearly 20 members in this family have been identified in mammals. [1] Nearly 20 members in this family have been identified in mammals.…”