Bcl2 family

Eman abd El-raouf ahmad Youssef

The content

definitionApoptosis regulator Bcl-2 is a family of

evolutionarily related proteins. These proteins govern mitochondrial outer membrane

permeabilization (MOMP) and can be either pro-apoptotic (Bax, BAD, Bak and Bok among

others) or anti-apoptotic (including Bcl-2 proper, 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.

Function:

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 into the cytosol which, once there, activates caspase-9 and caspase-3, leading to apoptosis. Although Zamzami et al. suggest that the release of cytochrome c is indirectly mediated by the PT pore on the inner mitochondrial membrane, strong evidence suggest an earlier implication of the MAC pore on the outer membrane.

Another theory suggests that Rho proteins play a role in Bcl-2, Mcl-1 and

Bid activation. Rho inhibition reduces the expression of anti-apoptotic Bcl-2

and Mcl-1 proteins and increases protein levels of pro-apoptotic Bid but had no

effect on Bax or FLIP levels. Rho inhibition induces caspase-9 and caspase-3-

dependent apoptosis of cultured human endothelial cells.

Rho proteins

Rho GTPases activation/deactivation cycle. Rho GTPases are

molecular switches that cycle between an

inactive GDP-bound and an active GTP-

bound state. Activation of Rho GTPases occurs by stimulation with a

guanine exchange factor (GEF) that causes the release of GDP and

the binding of GTP .

Structure:

structural studies have been performed on six Bcl-2 family members encompassing both anti- (Bcl-x(L), Bcl-2, KSHV-Bcl-2, Bcl-w) and pro-apoptotic (Bax, Bid) members .

structureAll proteins belonging to the Bcl-2 family contain either a BH1, BH2, BH3 or BH4 domain. All anti-apoptotic proteins contain BH1 and BH2 domains, some of them contain an additional N-terminal BH4 domain (Bcl-2, Bcl-x(L), Bcl-w), On the other hand, all pro-apoptotic proteins contain a BH3 domain necessary for dimerization with other proteins of Bcl-2 family and crucial for their killing activity, some of them also contain BH1 and BH2 domains (Bax, Bak). The BH3 domain is also present in some anti-apoptotic protein, such as Bcl-2 or Bcl-x(L).

BH3-only family of proteins includes those of the Bcl-2 family proteins, which contain only a single BH-domain. The BH3-only family members play a key

role in promoting apoptosis. The BH3-only family members

are Bim, Bid, BAD and others. Various apoptotic stimuli induce expression and/or activation of specific BH3-only family members, which translocate to the mitochondria and initiate Bax/Bak-dependent apoptosis.

Ex.Anti apoptotic B-cell lymphoma-extra large (Bcl-xl)

B-cell lymphoma-extra large (Bcl-xl) is a transmembrane molecule in the mitochondria. It is a member of the Bcl-2 family of proteins, and acts as a pro-survival protein by preventing

the release of mitochondrial contents such as cytochrome c, if more Bcl-xL is present, pores are non-permeable and the cell survives. However, if Bax and Bak become activated, and Bcl-xL is

sequestered away by gatekeeper BH3-only factors (e.g. Bim), causing a pore to form, cytochrome c is released leading to initiation of caspase cascade leading to apoptotic events.

Role of(Bcl-xl)

Bcl-2Bcl-2 (B-cell lymphoma 2), encoded by the BCL2 gene, is the founding member of the Bcl-2 family of regulator proteins that regulate cell death (apoptosis), by either inducing (pro-apoptotic) it or inhibiting it (anti-apoptotic).Bcl-2 is specifically considered as an important anti-apoptotic protein and is thus classified as an oncogene.

Bcl-2 derives its name from B-cell lymphoma 2, as it is the second member of a range of proteins initially described in chromosomal translocations involving chromosomes 14 and 18 in follicular lymphomas.

Role in disease:

Damage to the Bcl-2 gene has been identified as a cause of a number of cancers, including melanoma, breast, prostate, chronic lymphocytic leukemia, and lung cancer, and a possible cause of schizophrenia and autoimmunity. It is also a cause of resistance to cancer treatments.

Cancer occurs as the result of a disturbance in the homeostatic balance between cell growth and cell death. Over-expression of anti-apoptotic genes, and under-expression of pro-apoptotic genes, can result in the lack of cell death that is characteristic of cancer. An example can be seen in lymphomas.

Targeting BCL-2 family proteins for cancer therapy.

Pro-apoptotic proteins

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http:// . . / /95/5/2603/ 5. ://www pnas org content F exphttp. . / / /1847 .flipper diff org app pathways ansion html

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