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The role of Bcl-2 in programmed cell death

The role of Bcl-2 in programmed cell death. Presented by Matt Medeiros. The Bcl-2 gene. Bcl-2 is a proto-oncogene found on chromosome 18 First discovered in B-cell leukemia

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The role of Bcl-2 in programmed cell death

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  1. The role of Bcl-2 in programmed cell death Presented by Matt Medeiros

  2. The Bcl-2 gene Bcl-2 is a proto-oncogene found on chromosome 18 First discovered in B-cell leukemia A translocation between chromosome 18 and chromosome 14 places Bcl-2 next to an enhancer sequence used for synthesizing antibodies. Since the primary function of B cells is to synthesize large amounts of antibodies, this enhancer causes excessive amounts of Bcl-2 protein to be created.

  3. Bcl-2 protein structure NMR determined structure X-ray crystallography structure

  4. Bcl-2 protein structure • Hydrophobic pocket made up of BH1-3 binds BH3 domains of proapoptotic members - determined by complexing with BH3 peptide • BH1 and BH2 domains essential for antiapoptotic function - mutations induced in these regions eliminated the antiapoptotic characteristic

  5. These proteins function together to either hinder or initiate apoptosis • Bcl-2 homology domains (BH) • BH1 and BH2 – allow heterodimerization with Bax • BH3 – allows hetero-/homodimerization with Bcl-2, Bcl-x • BH4 – allows binding of death regulatory proteins • Bad and Bid do not contain the hydrophobic sequence The Bcl-2 Family

  6. Structure of Bcl-xL with a BH3 peptide derived from Bak

  7. The same thing just differently

  8. Function of Bcl-2 • Bcl-2 is an apoptosis antagonist • The exact mechanism of inhibiting apoptosis by Bcl-2 is unknown, but there are some hypotheses. • To function properly Bcl-2 must be anchored to the membrane of the mitochondria. While in the membrane, it can bind Bax which is a protein involved in initiating the caspase cascade. In its bound state, Bax can not activate the cascade and apoptosis does not occur.

  9. Function of Bcl-2 • Bcl-2 forms a Bcl-2/Apaf-1/caspase complex which stops the initiation of the caspase cascade • Bcl-2 affects the permeability transition of the mitochondrial membrane. By creating an ion gradient it keeps cytochrome c and AIF (apoptosis inducing factor) inside the mitochondria. These compounds are factors that initiate apoptosis.

  10. Bcl-2 related disease • The most common disease directly caused by Bcl-2 translocation is Non-Hodgkin’s follicular lymphoma • Lymphoma is an accumulation of B cells in the lymphatic system, creating tumors • Bcl-2 is also implicated in many cancers, such as, breast cancer, prostate cancer, and leukemia • Bcl-2 also increases cell resistance to chemotherapy

  11. Further Research • Non-peptidic Inhibitors - Antimycin A - terphenyl derivative • Upcoming studies will test toxicity of the non-peptidic inhibitors - most normal cells do not require Bcl-2 for proper functioning - cancer cells seem to be more susceptible to apoptosis

  12. References Chinnaiyin, A.M. Interaction of CED-4 with CED-3 and CED-9: A molecular framework for cell death. Science, 275, 1997, 1122-1126. Kimball, John. Kimball’s Biology Pages. 2003. <http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/W /Welcome.html> Lichnovsky, V. Apoptosis and expression of Bcl-2 and Bax during early human embryogenesis. Scripta Medica. 2000, 73(4), 245-250. McBride, Chris. The Bcl-2 Family. University of British Columbia. <http://cord.ubc.ca/~steeves/~chris/cbmhome.htm> Oltvai, Z.N. Bcl-2 counters apoptosis by Bax heterodimerization dependent and independent mechanisms in T-cell lineages. 272(46), 1997, 29347-29355. Yang, Elizazbeth. Molecular Thonatopsis: A discussion of the Bcl-2 Family and Cell Death. Ziwei Huang. The chemical biology of apoptosis: exploring protein-protein interactions and the life and death of cells with small molecules. Chemistry and Biology. 2002; 9, 1059-72.

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