Bcl-2

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Crystal structure of BCL-2, isoform 1.
B-cell CLL/lymphoma 2
Identifiers
Symbol BCL2
HUGO 990
Entrez 596
OMIM 151430
RefSeq NM_000633
UniProt P10415
PDB 1G5M
Other data
Locus Chr. 18 q21.3

Bcl-2 is the prototype for a family of mammalian genes and the proteins they produce. They govern mitochondrial outer membrane permeabilisation (MOMP) and can be either pro-apoptotic (Bax, Bak and Bok among others) or anti-apoptotic (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.

Contents

[edit] Function of Bcl-2

There are a number of theories concerning how the Bcl-2 gene family exert their pro- or anti-apoptotic effect. An important one states that this is achieved by activation or inactivation of an inner mitochondrial permeability transition 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-apoptotic members) or inhibit (anti-apoptotic 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. 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.[1]

The members of the Bcl-2 family share one or more of the four characteristic domains of homology entitled the Bcl-2 homology (BH) domains (named BH1, BH2, BH3 and BH4). The BH domains are known to be crucial for function, as deletion of these domains via molecular cloning affects survival/apoptosis rates. The anti-apoptotic Bcl-2 proteins, such as Bcl-2 and Bcl-xL, conserve all four BH domains. The BH domains also serve to subdivide the pro-apoptotic Bcl-2 proteins 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 amphipathic 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 mitochondrial outer membrane permeabilization (MOMP) have yet to be elucidated, but it is believed that the multidomain, pro-apoptotic Bcl-2 proteins can activate MOMP directly, a process that is inhibited by the binding of anti-apoptotic Bcl-2 proteins. In contrast, the BH3-only, pro-apoptotic Bcl-2 proteins activate MOMP indirectly by binding the anti-apoptotic Bcl-2 proteins, freeing the multidomain, pro-apoptotic Bcl-2 proteins to activate MOMP.

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.

[edit] 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. 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-apoptotic bcl-2 protein.[2] 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.

[edit] 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.[3]

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-xL, known as ABT-737.[4]. ABT-737 is one among many so-called BH3 mimetic small molecule inhibitors (SMI) targeting Bcl-2 and Bcl-2-related proteins such as Bcl-xL and Mcl-1, which may prove valuable in the therapy of lymphoma and other blood cancers.[5].

[edit] See also

[edit] References

  1. ^ 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.
  2. ^ 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.
  3. ^ 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.
  4. ^ Oltersdorf T, et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 435:677-681. PMID: 15902208
  5. ^ John C. Reed, and Maurizio Pellecchia, "Apoptosis-based therapies for hematologic malignancies", Blood. 106(2):408-418 (2005). PMID: 15797997

[edit] External links

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Oncogenes/Proto-oncogenes

c-Akt - c-Bcl-2 - c-ErbB (HER2/neu, Her 3) - AP-1 (c-Fos, c-Jun) - c-Mdm2 - c-Met - c-Myc - c-Raf - c-Ras - c-Sis - c-Src

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