Protein Bcl

Adams JM. The Bcl-2 protein family arbiters of cell survival. Science 1998 281 1322-1326. 

Gao Z, Matsuo H, Wang Y, Nakago S, Maruo T (2001) Up-regulation by IGF-I of proliferating cell nuclear antigen and Bcl-2 protein expression in human uterine leiomyoma cells. J Clin Endocrinol Metab 86 5593-5599... 

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,... 

Vander Heiden, M.G., and Thompson, C.B., 1999, Bcl-2 proteins Regulators of apoptosis or of mitochrondrial homeostasis , Nature Cell Biology 1 E209-216. 

Y. Saintigny, A. Dumay, S. Lambert and B. S. Lopez, A novel role for the Bcl-2 protein family specific suppression of the RAD51 recombination pathway, Embo /., 2001, 20(10), 2596. 

Barhoom S, Sharon A, Bcl-2 proteins link programmed cell death with growth... 

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 Bcl-2 protein is a member of a protein family involved in regulation of the apoptotic program in mammalian cells (review Reed, 1997 Adams and Cory, 1998). At present, at least 15 members are known of the Bcl-2 family, which can have a negative or a positive effect on initiation of the apoptotic program. All Bcl-2 family members have at least one copy of a so-called BH motif (BH, Bcl-2 homolog), of which there are four types (BHl - BH4). 

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-... 

One family includes the Bax, Bak and Bok proteins that have a similar structure to the Bcl-2 protein. There is a link via the Bax protein to the tumor suppressor protein p53 (see 15.6). 

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. 

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.

An important transcriptional target of the p53 protein that can induce apoptosis is the bax gene. The Bax protein belongs to the family of Bcl-2 proteins (see 15.3.2) and has a proapototic effect. There is speculation that the p53-induced increase in Bax concentration leads to formation of ion pores in mitochondria and that cytochrome c is released into the cytosol via these pores. Cytochrome c then functions as a cofactor which, together with Apafl protein, activates procaspase 8 and initiates the apoptotic program. 

Adams, J.M. and Cory, S. The BCl-2 protein family Arbiters of cell survival (1998) Science 281,... 

Fig. 1. Proposed mechanism of action of rituximab associated with the apoptosis pathway. Binding of rituximab with the CD20 antigen up-regulates the production of interleukin-10 (IL-10). The IL-10 autocrine loop down-regulates the expression of the bcl-2 protein, which inhibits the intrinsic pathway (or mitochondrial mediated pathway) of apoptosis. The mitochondrial pathway is induced by intracellular stress signals. The translocation of the bcl-2 protein into the mitochondria leads to the activation of caspase 9 via release of cytochrome c and apoptotic protease-activating factor 1. The other pathway, the extrinsic pathway (or death receptor mediated pathway) activates caspase 8. Subsequently, caspase 8 or 9 activates caspase 3, leading to programmed cell death (apoptosis).

Recent studies showed that rituximab down-regulates interleukin-10 (lL-10) in some lymphoma cell lines (17,18,19,20,21,22,23,24,25,26,27). IL-10 has a stimulatory function as an autocrine or paracrine growth factor for lymphoma cells (28). lL-10 is a known promoter of BCL2 expression in hematopoietic cells (29) as well as lymphoma cells (28). Rituximab is known to induce down-regulation of lL-10 expression and consequently of bcl-2 protein expression, making B-cells more susceptible to apoptotic signals (Fig. 1) (30,31,32). However, the implication of lL-10 on clinical outcome after rituximab therapy is still unclear. 

Umemura, S., Kawai, K., Osamura, Y., and Tsutsumi, Y. 1995. Antigen retrieval for bcl-2 protein in formalin-fixed, paraffin-embedded sections. Pathol. Internal. 45 103-107. 

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