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Bcl2 family
The Bcl-2 family is a group of evolutionarily related proteins that regulate apoptosis by either inducing it (pro-apoptotic) or inhibiting it (anti-apoptotic). There are 25 known genes in the family. They govern mitochondrial outer membrane permeabilization and the release of cytochrome c. Bcl-2 family proteins contain BH domains and either promote or inhibit apoptosis. Anti-apoptotic proteins like Bcl-xL prevent pore formation and cytochrome c release, while pro-apoptotic proteins like Bax can form pores, leading to caspase activation and cell death. Targeting specific Bcl-2 proteins may help treat cancers characterized by abnormal apoptosis regulation.
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Bcl2 family
- 2. Bcl2 family Eman abdEl-raouf ahmad Youssef
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- 4. definition Apoptosis regulator Bcl-2is 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.
- 7. Function: There are anumber 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 (proapoptotic 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.
- 8. Another theory suggeststhat 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-3dependent apoptosis of cultured human endothelial cells.
- 9. Rho proteins Rho GTPases activation/deactivationcycle. 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.
- 11. Structure: structural studies havebeen 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.
- 12. structure All proteins belongingto 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).
- 13. BH3-only family ofproteins 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.
- 15. Ex.Anti apoptotic B-celllymphoma-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.
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- 17. Bcl-2 Bcl-2 (B-cell lymphoma2), 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 (antiapoptotic).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.
- 18. Targeting BCL-2 familyproteins for cancer therapy.
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