Proteopedia - User contributions [en]

B-cell lymphoma protein

2009-10-05T05:37:19Z

Colin Ridenour:

B-cell lymphoma protein

2009-10-05T05:28:13Z

Colin Ridenour:

{{STRUCTURE_1g5m | PDB=1g5m | SCENE= }}

==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,[1] strong evidence suggest an earlier implication of the MAC pore on the outer membrane.[2][3]
Bcl-2 family[4]

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.[5]

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) (see the figure on the left). 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. Within the mitochondria are apoptogenic factors (cytochrome c, Smac/DIABLO, Omi) that if released activate the executioners of apoptosis, the caspases.[6] Depending on their function, once activated, Bcl-2 proteins either promote the release of these factors, or keep them sequestered in the mitochondria. Whereas the activated pro-apoptotic Bak and/or Bax would form MAC and mediate the release of cytochrome c, the anti-apoptotic Bcl-2 would block it, possibly through inhibition of Bax and/or Bak.[7]

==Role in disease==

The Bcl-2 gene has been implicated in a number of cancers, including melanoma, breast, prostate, and lung carcinomas, as well as schizophrenia and autoimmunity. 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.

Cancer is one of the world's leading causes of death and occurs when the homeostatic balance between cell growth and death is disturbed. Research in cancer biology has discovered that a variety of aberrations in gene expression of anti-apoptotic, pro-apoptotic and BH3-only proteins can contribute to the many forms of the disease. An interesting example can be seen in lymphomas. The over-expression of the anti-apoptotic Bcl-2 protein in lymphocytes alone did not act in an oncogenic manner. But simultaneous overexpression of Bcl-2 and the protooncogene myc may produce aggressive B-cell malignancies including lymphoma.[8] In follicular lymphoma, a chromosomal translocation commonly 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 bcl-2.[9] This decreases the propensity of these cells for undergoing apoptosis.

Apoptosis also plays a very active role in regulating the immune system. When it is functional, it can cause immune unresponsiveness to self-antigens via both central and peripheral tolerance. "In the case of defective apoptosis, it may contribute to etiological aspects of autoimmune diseases.[10] The autoimmune disease, type 1 diabetes can be caused by defective apoptosis, which leads to aberrant T cell AICD and defective peripheral tolerance. Due to the fact that dendritic cells (DCs) are of the most important antigen presenting cells of the immune system, their activity must be tightly regulated by such mechanisms as apoptosis. "Researchers have found that mice containing DCs that are Bim -/-, thus unable to induce effective apoptosis, obtain autoimmune diseases more so than those that have normal DCs.[10] Other studies have shown that the lifespan of DCs may be controlled by factors such as a timer dependent on anti-apoptotic Bcl-2.[10] These investigations illuminate the importance of regulating antigen presentation as mis-regulation can lead to autoimmunity.

Apoptosis plays a very important role in regulating a variety of diseases that have enormous social impacts. For example, schizophrenia is a neurodegenerative disease that may result from an abnormal ratio of pro- and anti-apoptotic factors.[11] There is some evidence that this defective apoptosis may result from abnormal expression of Bcl-2 and increased expression of caspase-3.[11]

Further research into the family of Bcl-2 proteins will provide a more complete picture on how these proteins interact with each other to promote and inhibit apoptosis. An understanding of the mechanisms involved will help discover potential treatments such as inhibitors to target over-expressed proteins that may lead to new therapies in cancer, autoimmune conditions, and neurological diseases.

==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.[12]

These have shown successful results in Phase I/II trials for lymphoma, and a large Phase III trial is currently underway[13]

Genasense did not receive FDA approval after disappointing results in a melanoma trial.

Abbott has recently described a novel inhibitor of Bcl-2, Bcl-xL and Bcl-w, known as ABT-737.[14] 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 Bcl-w but not A1 and Mcl-1, which may prove valuable in the therapy of lymphoma and other blood cancers.[15]

B-cell lymphoma protein

2009-10-05T05:19:47Z

Colin Ridenour: New page: ==This is a placeholder== This is a placeholder text to help you get started in placing a Jmol applet on your page. At any time, click "Show Preview" at the bottom of this page to see how...

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{{STRUCTURE_3cin | PDB=1g5m | SCENE= }}

==='''Function''' (I)===

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,[1] strong evidence suggest an earlier implication of the MAC pore on the outer membrane.[2][3]
Bcl-2 family[4]

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.[5]

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) (see the figure on the left). 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. Within the mitochondria are apoptogenic factors (cytochrome c, Smac/DIABLO, Omi) that if released activate the executioners of apoptosis, the caspases.[6] Depending on their function, once activated, Bcl-2 proteins either promote the release of these factors, or keep them sequestered in the mitochondria. Whereas the activated pro-apoptotic Bak and/or Bax would form MAC and mediate the release of cytochrome c, the anti-apoptotic Bcl-2 would block it, possibly through inhibition of Bax and/or Bak.[7]

==Role in disease==

The Bcl-2 gene has been implicated in a number of cancers, including melanoma, breast, prostate, and lung carcinomas, as well as schizophrenia and autoimmunity. 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.

Cancer is one of the world's leading causes of death and occurs when the homeostatic balance between cell growth and death is disturbed. Research in cancer biology has discovered that a variety of aberrations in gene expression of anti-apoptotic, pro-apoptotic and BH3-only proteins can contribute to the many forms of the disease. An interesting example can be seen in lymphomas. The over-expression of the anti-apoptotic Bcl-2 protein in lymphocytes alone did not act in an oncogenic manner. But simultaneous overexpression of Bcl-2 and the protooncogene myc may produce aggressive B-cell malignancies including lymphoma.[8] In follicular lymphoma, a chromosomal translocation commonly 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 bcl-2.[9] This decreases the propensity of these cells for undergoing apoptosis.

Apoptosis also plays a very active role in regulating the immune system. When it is functional, it can cause immune unresponsiveness to self-antigens via both central and peripheral tolerance. "In the case of defective apoptosis, it may contribute to etiological aspects of autoimmune diseases.[10] The autoimmune disease, type 1 diabetes can be caused by defective apoptosis, which leads to aberrant T cell AICD and defective peripheral tolerance. Due to the fact that dendritic cells (DCs) are of the most important antigen presenting cells of the immune system, their activity must be tightly regulated by such mechanisms as apoptosis. "Researchers have found that mice containing DCs that are Bim -/-, thus unable to induce effective apoptosis, obtain autoimmune diseases more so than those that have normal DCs.[10] Other studies have shown that the lifespan of DCs may be controlled by factors such as a timer dependent on anti-apoptotic Bcl-2.[10] These investigations illuminate the importance of regulating antigen presentation as mis-regulation can lead to autoimmunity.

Apoptosis plays a very important role in regulating a variety of diseases that have enormous social impacts. For example, schizophrenia is a neurodegenerative disease that may result from an abnormal ratio of pro- and anti-apoptotic factors.[11] There is some evidence that this defective apoptosis may result from abnormal expression of Bcl-2 and increased expression of caspase-3.[11]

Further research into the family of Bcl-2 proteins will provide a more complete picture on how these proteins interact with each other to promote and inhibit apoptosis. An understanding of the mechanisms involved will help discover potential treatments such as inhibitors to target over-expressed proteins that may lead to new therapies in cancer, autoimmune conditions, and neurological diseases.

==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.[12]

These have shown successful results in Phase I/II trials for lymphoma, and a large Phase III trial is currently underway[13]

Genasense did not receive FDA approval after disappointing results in a melanoma trial.

Abbott has recently described a novel inhibitor of Bcl-2, Bcl-xL and Bcl-w, known as ABT-737.[14] 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 Bcl-w but not A1 and Mcl-1, which may prove valuable in the therapy of lymphoma and other blood cancers.[15]

Ann taylor sandbox 5

2009-09-01T14:56:44Z

Colin Ridenour:

{{Seed}}
[[Image:3d06.jpg|left|200px]]


{{STRUCTURE_3d06| PDB=3d06 | SCENE= }}

==='''Human p53 core domain with hot spot mutation R249S''' (I)===

The tumor suppressor protein p53 is mutated in more than 50% of invasive cancers. About 30% of the mutations are found in six major "hot spot" codons located in its DNA binding core domain. To gain structural insight into the deleterious effects of such mutations and their rescue by suppressor mutations, we determined the crystal structures of the p53 core domain incorporating the hot spot mutation <scene name='Ann_taylor_sandbox_5/R249s/1'>R249S</scene>, the core domain incorporating R249S and a second-site suppressor mutation H168R (referred to as the double mutant R249S/H168R) and its sequence-specific complex with DNA and of the triple mutant R249S/H168R/T123A. The structural studies were accompanied by transactivation and apoptosis experiments. The crystal structures show that the region at the vicinity of the mutation site in the R249S mutant displays a range of conformations [wild-type (wt) and several mutant-type conformations] due to the loss of stabilizing interactions mediated by R249 in the wt protein. As a consequence, the protein surface that is critical to the formation of functional p53-DNA complexes, through protein-protein and protein-DNA interactions, is largely distorted in the mutant conformations, thus explaining the protein's "loss of function" as a transcription factor. The structure of this region is restored in both R249S/H168R and R249S/H168R/T123A and is further stabilized in the complex of R249S/H168R with DNA. Our functional data show that the introduction of H168R as a second-site suppressor mutation partially restores the transactivation capacity of the protein and that this effect is further amplified by the addition of a third-site mutation T123A. These findings together with previously reported data on wt and mutant p53 provide a structural framework for understanding p53 dysfunction as a result of oncogenic mutations and its rescue by suppressor mutations and for a potential drug design aimed at restoring wt activity to aberrant p53 proteins.

Structural basis of restoring sequence-specific DNA binding and transactivation to mutant p53 by suppressor mutations., Suad O, Rozenberg H, Brosh R, Diskin-Posner Y, Kessler N, Shimon LJ, Frolow F, Liran A, Rotter V, Shakked Z, J Mol Biol. 2009 Jan 9;385(1):249-65. Epub 2008 Oct 30. PMID:18996393

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

==Disease==
Known disease associated with this structure: Adrenal cortical carcinoma OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170 191170]], Breast cancer OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170 191170]], Colorectal cancer OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170 191170]], Hepatocellular carcinoma OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170 191170]], Histiocytoma OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170 191170]], Li-Fraumeni syndrome OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170 191170]], Multiple malignancy syndrome OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170 191170]], Nasopharyngeal carcinoma OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170 191170]], Osteosarcoma OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170 191170]], Pancreatic cancer OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170 191170]], Thyroid carcinoma OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=191170 191170]]

==About this Structure==
3D06 is a 1 chain structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3D06 OCA].

==Reference==
<ref group="xtra">PMID:18996393</ref><references group="xtra"/>
[[Category: Homo sapiens]]
[[Category: Frolow, F.]]
[[Category: Rozenberg, H.]]
[[Category: Shakked, Z.]]
[[Category: Shimon, L J.W.]]
[[Category: Suad, O.]]
[[Category: Acetylation]]
[[Category: Activator]]
[[Category: Alternative splicing]]
[[Category: Anti-oncogene]]
[[Category: Apoptosis]]
[[Category: Cell cycle]]
[[Category: Covalent protein-rna linkage]]
[[Category: Cytoplasm]]
[[Category: Disease mutation]]
[[Category: Dna-binding]]
[[Category: Endoplasmic reticulum]]
[[Category: Glycoprotein]]
[[Category: Host-virus interaction]]
[[Category: Li-fraumeni syndrome]]
[[Category: Loop-sheet-helix motif]]
[[Category: Metal-binding]]
[[Category: Methylation]]
[[Category: Mutant protein]]
[[Category: Nucleus]]
[[Category: P53]]
[[Category: Phosphoprotein]]
[[Category: Polymorphism]]
[[Category: Transcription]]
[[Category: Transcription regulation]]
[[Category: Ubl conjugation]]
[[Category: Zinc]]

''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 21 10:44:12 2009''