Apoptosis family members

BH3 domain) of the BH3-only proteins binds to other Bcl-2 family members thereby influencing their conformation. This interaction facilitates the release of cytochrome C and other mitochondrial proteins from the intermembrane space of mitochondria. Despite much effort the exact biochemical mechanism which governs this release is not yet fully understood. The release of cytochrome C facilitates the formation of the apoptosome, the second platform for apoptosis initiation besides the DISC. At the apoptosome which is also a multi-protein complex the initiator caspase-9 is activated. At this point the two pathways converge. 

Gross A, McDonnell JM, Korsmeyer SJ (1999) BCL-2 family members and the mitochondria in apoptosis. Genes Dev 13 1899-1911... 

Once apoptosis is triggered, a stereotyped sequence of premitochondrial events occurs that executes the cell death process. In many cases proteins and/or lipid mediators that induce changes in mitochondrial membrane permeability and calcium regulation are produced or activated. For example, the pro-apoptotic Bcl-2 family members Bax, Bad and Bid may associate with the mitochondrial membrane and modify its permeability. Membrane-derived lipid mediators such as ceramide and 4-hydroxynonenal can also induce mitochondrial membrane alterations that are critical for the execution of apoptosis. 

Antiapoptotic proteins. There are many different intracellular proteins that can prevent apoptosis by inhibiting specific steps in the cell death process. These include Bcl-2 family members such as Bcl-2 and Bcl-xL which can stabilize (mitochondrial, ER and plasma) membranes (Bcl-2 may also have intrinsic antioxidant activity). Other proteins, IAPs such as XIAP (X-linked) and NIAP (neuronal), which can directly inhibit caspases [31]. Additional examples of antiapoptotic proteins include protease inhibitors such as calpastatin, and protein chaperones such as GRP-78 and heat shock protein (HSP)-70. 

Regulation of programmed cell death (apoptosis) is not only important in normal cell development and homeostasis [1, 2], but also during the process of carcinogenesis [3], Apoptosis is suppressed in most cancer cells and induction of apoptosis is one cancer treatment strategy [4], There are many processes and factors that can be modulated to induce cancer cell apoptosis, such as regulation of factors involved in cell cycle arrest [5], protein kinase modulation [6], caspase family activation [7], and the balance in expression between Bcl-2 family members [8],... 

Zhou J, Zhang S, Ong CN, Shen HM. (2006) Critical role of pro-apoptotic Bcl-2 family members in andrographolide induced apoptosis in human cancer cells. Biochem Pharmacol 14 132-144. 

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. 

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. 

In PC3 cells, curcumin down-regulates MDM2 proteins and mRNA. enhances the expression of the tumor suppressor p21 and inhibits IkBoc [Guo et al., 2006 Li et al., 2007b]. Curcumin can also inhibit prostate cancer via the Akt pathway or the induction of apoptosis by Bcl-2 family members and mitochondrial p53 [Chaudhary and Hruska, 2003 Deeb et al., 2007 Shankar et al., 2007]. 

Sustained cytosolic Ca2+ overload usually results in a different route leading to cell death. It mainly relies on the activation of the calcium/calmodulin (CaM)-dependent phosphatase, calcineurin. Calcineurin-catalyzed dephosphorylation promotes apoptosis by regulating the activity of a number of downstream targets, including the pro-apoptotic Bcl-2 family member, Bad (Wang, et al., 1999), and transcription factors of the NFAT (nuclear factor of activated T cells) family (Rao, et al., 1997). There are also other Ca2+-dependent enzymes contributing to the apoptotic events, and they include several DNA-degrading endonucleases (Robertson, et al., 2000) and Ca2+-activated cystein proteases of the calpain family essential for the enzymatic activation of the crucial pro-apoptotic effectors (Altznauer, et al., 2004). 

Concern over the role of Bax in angiotensin II-mediated apoptosis has led to a modified version of the Grishko hypothesis (Figure 6.8). The modified hypothesis was influenced by the discovery that angiotensin Il-induced apoptosis proceeds via the mitochondrial permeability transition (MPT) (Ricci et al. 2005). Although Bcl-2 family members can modulate the activity of the MPT pore (Shimizu et al. 1999 Rostovtseva et al. 2004), regulation of the MPT pore by oxidative stress may be... 

Harris CA, Johnson EM Jr (2001), BH3-only Bcl-2 family members are coordinately regulated by the JNK pathway and require Bax to induce apoptosis in neurons, J. Biol. Chem. 276 37754-37760. 

Zong WX, Lindsten T, Ross AJ, MacGregor GR, Thompson CB (2001), BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak, Genes Dev. 15 1481-1486. 

Experiments in this laboratory identified apoptosis as a consequence of the action of cisplatin and many other anticancer agents [50-52], Many authors have subsequently misquoted these results when suggesting that cisplatin kills by apoptosis, and that suppression of apoptosis is a mechanism of resistance. It should be evident by now that apoptosis is better defined as a consequence of the mechanism of action of cisplatin and a failure of the mechanisms of resistance. Apoptosis is certainly not an alternative to the formation of DNA cross-links, nor to the cell-cycle perturbations that result these are still essential events in the initiation phase of apoptosis. The mechanisms of resistance to cisplatin still include reduced drug accumulation, reduced DNA platination, and altered DNA repair. However, apoptosis provides a framework for understanding the complete pathway from initial insult to eventual death of a cell. It provides the realization that there are additional factors that influence cell survival and death. Expression of Bcl-2 family members or changes in signal transduction pathways impact... 

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