Bcl-2 family

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. 

Van Delft MF, Huang DC (2006) How the Bcl-2 family of proteins interact to regulate apoptosis. Cell Res 16 203-213... 

Bcl-x is a gene in the bcl-2 family that inhibits apoptosis after trophic factor deprivation in vitro. 

BID is a member oftheBcl-2 gene family, which encode proteins that function either to promote apoptosis or to inhibit apoptosis as in the proteins derived from Bcl-2. These proteins can exist as monomers or they can dimerize. For example, if two promoting Bcl-2 family proteins dimerize then apoptosis will be greatly enhanced. Conversely, if dimerization of an inhibitory and promotor protein occurs, then the effects are cancelled out. The Bcl-2 family of proteins are localized to the outer mitochondrial or outer nuclear membranes. 

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

PALOZZA P, SERINI S, MAGGIANO N, ANGELINI M, BONINSEGNA A, DI NICUOLO F, RANELLETTI F O and CALVIELLO G (2002) Induction of cell cycle arrest and apoptosis in human colon adenocarcinoma cell lines by P-carotene through down-regulation of cyclin A and Bcl-2 family proteins , Carcinogenesis, 23, 11-18. 

Lee, J.I. et al., Beta-lapachone induces growth inhibition and apoptosis in bladder cancer cells by modulation of Bcl-2 family and activation of caspases, Exp. Oncol., 28, 30, 2006. 

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. 

S. Akahani, P. Nangia-Makker, H. Inohara, H.-R. Kim, and A. Raz, Galectin-3 A novel antiapoptotic molecule with a functional BH1 (NHGR) domain of bcl-2 family, Cancer Res., 57 (1997) 5272-5276. 

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. 

Manji, H. K. and Chen, G. PKC, MAP kinases and the bcl-2 family of proteins as long-term targets for mood stabilizers. Mol Psych. 7(Suppl 1) S46-56, 2002. 

Rosenthal, D.S., et al., Mechanisms of JP-8 jet fuel cell toxicity B. Induction of necrosis in skin fibroblasts and keratinocytes and modulation of levels of Bcl-2 family members, Toxicol. Appl. Pharmacol., 171, 107, 2001. 

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],... 

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,... 

A link between the pathways controlled by the TNF-receptor family members and the mitochondrial pathway has been identified. It has been shown that caspase-8 can cleave Bid, resulting in the formation of truncated Bid (tBid), a death-inducing member of the Bcl-2 family (Gross et al, 1999 Li et al, 1998 Luo et al., 1998). Bid activation appears not to be essential in cells with high amoimts of caspase-8 in the death receptor complex but may be required to amplify the cascade in cells with low amounts of caspase-8 in the death receptor complex. 

Most of the responses which lead to cytochrome c release are triggered by activated proapoptotic members of the Bcl-2 family which are directed to mitochondria, where they insert into the outer membrane. What mediates the specific targeting of these proteins to mitochondria, hi a recent work, Lutter et al. (2000) investigated this question using the proapoptotic Bcl-2 member (tBid) as a tool. These authors estabhshed a hposome model for cytochrome c release and recreated the lipid constitution of mitochondrial outer... 

Shimizu S., Naiita, M., andTsujimoto, Y., 1999, Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC, Nature 399 483-487. 

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