Bcl-2
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Bcl-2 is the prototype for a family of genes that can be either pro-apoptopic (Bax, Bak and Bok among others) or anti-apoptopic (including Bcl-2, Bcl-xL, Bcl-w also 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 in particular forms of lymphoma.
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Gene function
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 memberts) 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 on the PT pore of the inner mitochondrial membrane, linking the theories.
Role in disease
The Bcl-2 gene has been implicated in a number of cancers, including melanoma, breast, prostrate 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 (IgH) locus. This fusion gene is deregulated, leading to the transcription of excessively high levels of anti-apoptopic Bcl-2 protein (Hockenbery et al 1990). This decreases the propensity of these cells for undergoing apoptosis.
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 cells (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).
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.
- Hockenbery D, Nunez G, Milliman C, Schreiber RD, Korsmeyer SJ. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 1990;348:334-6. PMID 2250705.
- 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.