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Bcl-2

Bcl-2. Sarah A. Norris. Apoptosis. Programmed cell death. http://virtuallaboratory.net/Biofundamentals/lectureNotes/Topic5-4_CellDeath.htm. http://upload.wikimedia.org/wikipedia/commons/8/8a/Bcl-2_Family.jpg. Bcl-2 Structure. Encodes an integral membrane protein.

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Bcl-2

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  1. Bcl-2 Sarah A. Norris

  2. Apoptosis • Programmed cell death http://virtuallaboratory.net/Biofundamentals/lectureNotes/Topic5-4_CellDeath.htm

  3. http://upload.wikimedia.org/wikipedia/commons/8/8a/Bcl-2_Family.jpghttp://upload.wikimedia.org/wikipedia/commons/8/8a/Bcl-2_Family.jpg

  4. Bcl-2 Structure • Encodes an integral membrane protein. • Localized to outer membranes of mitochondria, endoplasmic reticulum, and nuclear envelope. • Targeted by 21 C-terminal hydrophobic amino acids

  5. Structure • Globular bundle of 5 amphipathic α-helices surround 2 central hydrophobic α-helices • Hydrophobic groove formed by BH1, BH2, BH3 http://opm.phar.umich.edu/images/proteins/1g5m.gif, (Fesik 2005)

  6. Apoptosis: the stress pathway Cell damage mitochondrial damage BCL-2 Mitochondria Cytochrome -c Procaspase 9 APAF 1 Apoptosome Caspase 9 Caspases 3, 6, 7 (Ashkenazi 2002)

  7. How does Bcl-2 inhibit Apoptosis? • Binds Apaf-1, inhibiting Caspase-9 binding

  8. How does Bcl-2 inhibit Apoptosis? • Prevents release of cytochrome c from mitochondria

  9. Dimerization deactivation activation Bad deactivation (competitive inhibition) http://www.bentham.org/cmm/sample/cmm1-1/Kornbluth/Kornbluth-fig4-pg97.jpg

  10. Biological Role

  11. Biological Role (Lewis 2000)

  12. Homozygous null mutant http://www.informatics.jax.org/javawi2/servlet/WIFetch?page=markerDetail&key=529

  13. Bcl-2: Discovery • Human proto-oncogene • Discovered in t(14;18) translocations in B-Cell Lymphomas and leukemias.

  14. Cancer (Tsujimoto 1984)

  15. Cancer • Overexpression contributes to tumorigenesis by inhibiting apoptosis • Mutations are implicated in melanoma, breast, prostate, and lung carcinomas • Facilitates metastasis • Dampens response to chemotherapy and radiation

  16. Treatment • Down-regulation can increase chemosensitivity • Genasense – an antisense oligonucleotide drug

  17. References • Ashkenazi A. Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nat Rev Cancer, 2, 420–430 (2002). • Cleary ML, Smith SD, et. al. Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation. Cell,47, 19-28 (1986). • Cory S, Adams J. The Bcl2 Family: Regulators of the cellular life-or death switch. Nat Rev Cancer, 2, 647-656 (2002). • Fesik SW, Promoting apoptosis as a strategy for cancer drug discovery. Nat Rev Cancer,5, 876-885 (2005). • Haldar S, Beatty C, et. al. The bcl-2 gene encodes a novel G protein. Nature342, 195 - 198 (1989). • Horvitz HR. Genetic control of programmed cell death in the nematode Caenorhabditis elegans. Cancer Res. 59, S1701–S1706 (1999). • Lewis K. Programmed death in bacteria. Microbiol Mol Biol Rev 64, 503-514 (2000). • Reed JC, Tsujimoto Y, et. Al. Regulation of bcl-2 Proto-Oncogene Expression During Normal Human Lymphocyte Proliferation. Science,236, 1295-1299 (1987). • Tsujimoto Y. Cloning of the Chromosome Breakpoint of Neoplastic B Cells with the t(14;18) Chromosome Translocation. Science, 226, (1984). • Vaux DL. Weissman, I. L. & Kim, S. K. Prevention of programmed cell death in Caenorhabditis elegans by human BCL-2. Science 258, 1955–1957 (1992).

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