This is contradictory to is assumed given the anti-apoptotic function of Bcl-2: upregulated Bcl-2 expression should be more likely to be a marker of a more aggressive tumor phenotype. The most plausible explanation for this paradoxical finding is the fact that Bcl-2 not only has an anti-apoptotic function, it can also exert a distinct negative influence on cell cycle progression, Sorafenib which can eventually slow down tumor growth. This may explain the survival benefit for several patients with upregulated Bcl-2 expression.83�C85,89 Whether the anti-cell cycle progression or the anti-apoptotic role of Bcl-2 predominates during tumorigenesis may depend on disease stage. In early carcinogenesis, the anti-apoptotic function of Bcl-2 plays a large role, causing genetic alterations to accumulate.

In later stages, Bcl-2 functions more as a cell cycle progression inhibitor, lowering the rate of tumor proliferation. This hypothesis is supported by the inverse correlation between Bcl-2 and the percentage of cells in S-phase found by Buglioni et al.83 The studies describing the prognostic relevance of Bcl-2 would therefore be more informative if disease stage and the expression of other family members were taken into account. This would provide us additional insight in the biological function and effects on the apoptotic pathway of Bcl-2, which will tremendously improve the interpretation of the results. Table 5 Bcl-2 as a clinical prognostic marker.

Inhibitors of apoptosis family proteins and the execution of apoptosis The actual apoptotic cell death machinery, responsible for the execution of apoptosis and resulting in the morphological features characteristic of apoptosis, consists of a very complex cascade of interacting proteins. The key components include the caspase proteins, as described above. At many levels, regulation takes place to ensure appropriate functioning of the caspase machinery. Key regulators of the caspase cascade are the inhibitors of apoptosis proteins (IAPs) that exert their function through binding of activated caspases. Thus far, 8 IAPs have been identified in mammals, the most well-known being livin, X-linked inhibitor of apoptosis (XIAP), and survivin.26,91,92 All IAP family proteins have one or several specific Baculoviral IAP repeats (BIRs). They require at least one BIR to exert their anti-apoptotic function.

The function of the IAPs is also strictly regulated by their own set of inhibitors such as Smac/Diablo and Omi/HtrA2.26 Under normal circumstances, when apoptotic stimuli are present, cells release Smac/DIABLO from their mitochondria into the cytosol, where the complex exerts its pro-apoptotic effect by interacting with Carfilzomib the IAPs in order to release bound caspases into the cytosol.93 The most frequently studied IAP in our search results was survivin, likely because the role of survivin in apoptosis has been the subject of controversy over the last few years.