Bcl-2
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Bcl-2 is the prototype for a family of mammalian genes and the proteins they produce. They govern mitochondrial membrane permeabilisation (MMP) and can be either pro-apoptopic (Bax, Bak and Bok among others) or anti-apoptopic (including Bcl-2, Bcl-xL, and Bcl-w, among an assortment of others). There are a total of 25 genes in the Bcl-2 family known to date. Bcl-2 derives its name from B-cell lymphoma 2, as it is the second member of a range of proteins initially described as a reciprocal gene translocation in chromosomes 14 and 18 in follicular lymphomas.
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Function of Bcl-2
There are a number of theories concerning how the Bcl2 gene family exert their pro- or anti-apoptopic effect. An important one states that this is achieved by activation or inactivation of an inner mitochondrial permeability transition (PT) pore, which is involved in the regulation of matrix Ca2+, pH, and voltage. It is also thought that some Bcl-2 family proteins can induce (pro-apoptopic members) or inhibit (anti-apoptopic members) the release of cytochrome c in to the cytosol which, once there, activates caspase-9 and caspase-3, leading to apoptosis. Zamzami et al. (1998) suggest that the release of cytochrome c is in fact mediated by effects of the PT pore on the inner mitochondrial membrane, linking the theories.
The members of the Bcl-2 family share characteristic domains of homology entitled the Bcl-2 homology (BH) domains. The BH domains are known to be crucial for function, as deletion of these domains via molecular cloning affects survival/apoptosis rates. The BH domains also serve to further subdivde the pro-apoptotic group into those with several BH domains (e.g. Bax and Bak) or those proteins that have only the BH3 domain (e.g. Bid, Bim and Bad). The Bcl-2 family has a general structure that consists of a hydrophobic helix surrounded by ampipathic helices. Many members of the family have transmembrane domains. The site of action for the Bcl-2 family is mostly on the outer mitochondrial membrane (OMM). Within the mitochondria are apoptogenic factors (cytochrome c, Smac/DIABLO, Omi) that if released activate the executioners of apoptosis, the caspases. Depending on their function, once activated, Bcl-2 proteins either promote the release of these factors, or keep them sequestered in the mitochondria. The exact mechanisms surrounding Bcl-2 regulated MMP have yet to be elucidated.
The protein Bcl-2 is an anti-apoptotic protein that resides in the OMM and the membrane of the endoplasmic reticulum. Over expression of Bcl-2 is known to block cytochrome c release, possibly through the inhibition of Bax and Bak. The protein also conforms to the general structure of Bcl-2 proteins, with a transmembrane domain in its C-terminus.
Role in disease
The Bcl-2 gene has been implicated in a number of cancers, including melanoma, breast, prostate and lung carcinomas. It is also thought to be involved in resistance to conventional cancer treatment (Bast et al., 2000). This supports a role for decreased apoptosis in the pathogenesis of cancer.
In follicular B-cell lymphoma, a chromosomal translocation occurs between the fourteenth and the eighteenth chromosomes - t(14;18) - which places the Bcl-2 gene next to the immunoglobulin heavy chain locus. This fusion gene is deregulated, leading to the transcription of excessively high levels of anti-apoptopic bcl-2 protein (Vaux et al 1988). This decreases the propensity of these cells for undergoing apoptosis.
This protein is essential to the process of apoptosis because it suppresses the initiation of the cell-death process.
Targeted therapies
An antisense oligonucleotide drug Genasense (G3139) has been developed to target Bcl-2. An antisense DNA or RNA strand is non-coding and complementary to the coding strand (which is the template for producing respectively RNA or protein). An antisense drug is a short sequence of RNA which hybridises with and inactivates mRNA, preventing the protein from being formed.
It was shown that the proliferation of human lymphoma s (with t(14;18) translocation) could be inhibited by antisense RNA targeted at the start codon region of Bcl-2 mRNA. In vitro studies led to the identification of Genasense, which is complementary to the first 6 codons of Bcl-2 mRNA (Dias and Stein 2002).
These have shown successful results in Phase I/II trials for lymphoma, and a large Phase III trial is currently underway (Mavoromatis and Cheson 2004).
Genasense did not receive FDA approval after disappointing results in a melanoma trial.
Abbott has recently described a novel inhibitor of Bcl-2 and Bcl-x (Oltersdorf et al., 2005).
BIM
BIM is a protein from Bcl-2 protein family, BH3 subfamily. The BIM protein is produced by bim gene.
BIM protein inhibites PKCα and PKCε. [[1]]. BIM protein inhibites Bcl-2 so it is supports apoptosis (bim is proapoptic gene). Bim is probably activated by Myc or by p19Arf [[2]].
See also
References
- Dias N, Stein CA. Potential roles of antisense oligonucleotides in cancer therapy. The example of Bcl-2 antisense oligonucleotides. Eur J Pharm Biopharm 2002;54:263-9. PMID 12445555.
- Oltersdorf T, et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 435:677-681. PMID: 15902208
- Vaux DL, Cory S, Adams JM. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature 1988;335:440-2. PMID: 3262202.
- Mavromatis BH, Cheson BD. Novel therapies for chronic lymphocytic leukemia. Blood Rev 2004;18:137-48. PMID 15010151.
- Zamzami N, Brenner C, Marzo I, Susin SA, Kroemer G. Subcellular and submitochondrial mode of action of Bcl-2-like oncoproteins. Oncogene 1998;16:2265-82. PMID 9619836.