bcl2 family
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Bcl2 family
Eman abd El-raouf ahmad Youssef
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The content
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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.
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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.
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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.
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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 .
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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 .
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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).
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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.
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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.
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Role of(Bcl-xl)
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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.
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Targeting BCL-2 family proteins for cancer therapy.
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Pro-apoptotic proteins
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References:://http . . . . / /14996493www ncbi nlm nih gov pubmed
http:// . . / /95/5/2603/ 5. ://www pnas org content F exphttp. . / / /1847 .flipper diff org app pathways ansion html
http://www.jbc.org/content/275/40/31546.fullhttp://www-personal.umich.edu/~ino/List/2342.htmhttp://www.apoptosis.at/general.htmhttp://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.0060147http://www.nature.com/nchembio/journal/v9/n12/index.htmlhttp://www.broadinstitute.org/news/4119http://www.vanderbilt.edu/vicb/DiscoveriesArchives/mcl-1_inhibitors_offer_hope.htmlhttp://www.omicsonline.org/1948-593X/JBABM-04-034.php
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Thank you