Antiapoptotic Bcl-2 proteins

Proapototic signals direct these proteins to mitochondria where they compete with antiapoptotic members of the Bcl-2 family to regulate the cytochrome c release and to determine the fate of the cell life or death (Cosulich et al., 1999). Unlike proapoptotic proteins, the antiapoptotic Bcl-2 proteins reside in the outer mitochondrial membrane, anchored by a hydrophobic stretch of amino acids located at the COOH-termini,... 

The biochemical basis of the various activities of the Bcl-2 family members is only partially imderstood. The antiapoptotic Bcl-2 proteins may function by directly inhibiting the activation of the caspases (see 15.3.3). It is assumed that proapoptotic proteins interact with antiapoptotic proteins and halt their inhibition of apoptosis. 

Tang G, et al. Pyrogallol-based molecules as potent inhibitors of the antiapoptotic Bcl-2 proteins. J. Med. Chem. 2007 50 1723-1726. 

Leone M, Zhai D, Sareth S, Kitada S, Reed JC, Pellecchia M. Cancer prevention by tea polyphenols is linked to their direct inhibition of antiapoptotic Bcl-2-family proteins. Cancer Res 2003 63 8118-8121. 

The Bcl-2 protein was first identified as an oncoprotein coded by a gene affected by translocations of chromosomes 14 and 18 in B cell lymphomas. It was soon shown, however, that the Bcl-2 protein is not involved in regulation of the cell cycle, in contrast to many other oncoproteins, and thus does not fit into the classical oncogene picture. Furthermore, homology was estabhshed with the Ced9 protein of C. elegans, which has an antiapoptotic function in this organism. 

The antiapoptotic members of the Bcl-2 family (Bcl-2, BclX, BclW, Al, Mcl-l) inhibit apoptosis by various cytotoxic effects. At a minimum, they contain the motives BHl and BH2. Bcl-2 protein contains all fom BH motives. For the mechanism of the antiapoptotic function, see 15.3.4 and 15.4. 

The antiapoptotic function of the Bcl-2 protein has been clearly shown experimentally. Its overexpression can prevent initiation of the apoptotic program in various cell types. The oncogenic function of Bcl-2 protein, observed in association with its overex-... 

Various members of the Bcl-2 family can interact with another via the BH domains and form hetero-oligomeric complexes in which the different activities neutralize one another. The relationship of proapoptotic and antiapoptotic Bcl-2 family proteins thus helps to determine a cell s susceptibility to apoptosis. 

The antiapoptotic Bcl-2 family members control apoptosis by various mechanisms without directly binding to the caspases. Bcl-2 proteins can interact with cofactors and inhibit their activity. They can also act antiapoptotically by binding to mitochondria and interfering with release of cytochrome c. Furthermore, they can interact with other proapoptotic proteins, e.g. with propapoptotic members of their own family. 

Fig. 15.9. Antiapoptotic signalling by the PI3-kinase/Akt kinase pathway The PI3 kinase/Akt kinase pathway influences apoptosis via phosphorylation of the Bad protein, which is a member of the family of Bcl-2 proteins. Activation of the PI3-kinase pathway leads to Akt-kinase-catalyzed phosphorylation of Bad protein. Bad protein in its unphosphorylated form participates in activation of initiator caspases and thus has a proapoptotic effect. Phosphorylation of Bad protein by Akt kinase (or related kinases) has an antiapoptotic effect since phosphoryla-ted Bad protein is a binding substrate of 14-3-3 proteins. Bad is thus sequestered in an inactive state and is not available for triggering of apoptosis.

Members of the Bcl-2 protein family are key regulators of the mitochondrial step in apoptotic pathway (44). Upregulation of antiapoptotic Bcl-2 family members is commonly observed in many types of cancers and is well established to play a major... 

Fig. 15.3 The major pathways of apoptosis. The extrinsic pathway uses extracellular death ligands (Fas ligand, tumor necrosis factor (TNF)) to activate death receptors which pass the apoptotic signal to initiator caspases (e. g. capsase 8) and to the executioner caspases (e. g. caspase 3 caspase 7). In the execution phase of apoptosis, various cellular substrates are degraded leading to cellular collapse. The intrinsic pathway uses the mitochondria as a central component for activation of apoptosis. In this pathway, a multitude of intracellular signals including various stresses, DNA damage and inappropriate cell signaling lead to activation of the pro-apoptotic protein Bax which induces release of cytochrome c from mitochindria, formation of the apoptosome and activation of the initiator caspase 9. Finally, the executioner caspases are activated and cells are destructed by proteolysis. Apoptosis via this pathway can be controlled by various antiapoptotic proteins including the Bcl-2 protein and inhibitors of apoptosis.

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