Apoptosis and oncogenesis: give and take in the BCL-2 family
Introduction
For more than half a century, we have understood that cancer is a consequence of progressive mutations in the genome, resulting in the unregulated expansion of a clone of cells [1]. Several of these steps were functionally grouped into ‘hallmarks’ of cancer [2] and these were subsequently elaborated upon [3]. However, a contrasting viewpoint (or at least, a complementary one) holds that the core changes that convert a cell to a cancer are relatively basic: an increase in proliferation coupled to a decrease in cell death [4]. Many of the hallmarks, in this view, may be regarded as features of any growing tissue, although additional mutations can clearly contribute to the aggressiveness of the tumor. Here, we overview recent progress in the delineation of the mechanisms of cell death as they relate to cancer, and conversely, how features of cancer and its therapeutic manipulation relate to these mechanisms. In particular, we focus on one particular form of cell death, apoptosis, and the major way in which this occurs: the mitochondrial pathway of apoptosis. This avenue to cell death is controlled by proteins of the BCL-2 family, and our discussion is specifically geared to our emerging understanding of how these proteins work, and how this informs our thinking about oncogenesis.
Section snippets
Mitochondria as stepping-stones on the road to ruin
Most cell death in vertebrates occurs via the mitochondrial pathway of apoptosis, in which proteins of the BCL-2 family function to control the integrity of the outer membranes of mitochondria in the cell. When the interactions among these proteins results in apoptosis, the two pro-apoptotic BCL-2 effector proteins, BAX and BAK, disrupt this membrane in a process called mitochondrial outer membrane permeabilization (MOMP). If MOMP occurs, proteins present in the mitochondrial intermembrane
Stalking the killers
BAX and BAK are superficially redundant proteins required for MOMP. That is, in the absence of both, MOMP does not occur, and each is capable of permeabilizing lipid membranes. Such permeabilization appears to be in the form of large, round holes of 25–100 nm [26•] that may represent lipidic pores [27, 28, 29], and allow the diffusion of proteins through the membrane. However, it is not fully understood how BAX and BAK cause such permeabilization: although structural data exists for each in
Further complexity in the regulation of the BCL-2 proteins
BAX and BAK, as well as the anti-apoptotic proteins, are controlled at several steps in addition to their interactions with BH3-only proteins. Recent studies have highlighted some novel ways in which such regulation comes about. BAX can be inhibited by the function of the peptidyl-proline isomerase PIN1 [49], presumably affecting its conformation (although other possibilities certainly exist). BAX is also targeted by the E3 ligase IBRDC2 for ubiquitylation and degradation [50]. Intriguingly, an
The PUMA paradox
PUMA is a BH3-only protein that binds and inhibits all of the anti-apoptotic BCL-2 proteins [16, 17]. It is a direct transcriptional target of p53 and is also induced by FOXO3a under conditions of growth factor deprivation [77, 78, 79]. PUMA may also activate BAX and BAK [33, 34, 80], although it has been shown to promote MOMP predominantly through displacement of other proteins with this function from anti-apoptotic BCL-2 proteins [81]. Loss of PUMA accelerates Myc-induced lymphomagenesis [82,
Conclusion
The process of oncogenesis ensures that cancer cells display dysregulation of some apoptotic pathways, that is, those pathways that are engaged by the specific tumor suppressor mechanisms that would serve to limit tumorigenesis in these cells. As a consequence, tumor cells may actually be more sensitive to the engagement of other pathways of apoptosis than are primary cells, since tumor expansion requires only that cell death occur at a lower frequency than that of cell division. The
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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