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The Role of Bcl-2 in Apoptosis and Cancer

The Role of Bcl-2 in Apoptosis and Cancer. Eddie Alcorn. Bcl-2 aids in preventing apoptosis. Hanahan and Weinberg, Cell 100:57-70 (2000). Table of Contents. The cell machinery and jobs of Bcl-2 in a typical cell. How the absence of Bcl-2 impacts an organism during development.

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The Role of Bcl-2 in Apoptosis and Cancer

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  1. The Role of Bcl-2 in Apoptosis and Cancer Eddie Alcorn

  2. Bcl-2 aids in preventing apoptosis. Hanahan and Weinberg, Cell 100:57-70 (2000)

  3. Table of Contents The cell machinery and jobs of Bcl-2 in a typical cell How the absence of Bcl-2 impacts an organism during development The effect of Bcl-2 on tumorigenesis

  4. Bcl2 is part of a family of related proteins that play different roles inapoptosis. Cory, S., Adams, J.M. Nature 2, 647-656. (2002)

  5. Most cellular Bcl-2 is bound to the outer mitochondrial membrane. Cory, S., Adams, J.M. Nature 2, 647-656. (2002)

  6. At the membrane, Bcl-2 blocks Bax and Bak activity. Cory, S., Adams, J.M. Nature 2, 647-656. (2002)

  7. BH3-only protein binds and inhibits Bcl-2, discontinuing its obstruction to Bax and Bak activity. Cory, S., Adams, J.M. Nature 2, 647-656. (2002)

  8. Bax and Bak release Cytochrome C and Diablo from the mitochondria to induce apoptosis. Cory, S., Adams, J.M. Nature 2, 647-656. (2002)

  9. Table of Contents The cell machinery and jobs of Bcl-2 in a typical cell How the absence of Bcl-2 impacts an organism during development The effect of Bcl-2 on tumorigenesis

  10. In a Bcl-2 knockout mouse, • neonatal kidney and immune system are destroyed by cell suicide. • Melanocytes are driven to enter apoptosis, eventually yielding grey mice. Kamada, S et al. Figure 2A

  11. Experiments have shown that a Bcl-2 knockout mouse can be rescued by loss of a single allele in a BH3-only protein. BH3-only +/+ and Bcl2 -/- => Apoptosis BH3-only +/- and Bcl2 -/- => Rescue Cory, S., Adams, J.M. Nature 2, 647-656. (2002)

  12. Table of Contents The cell machinery and jobs of Bcl-2 in a typical cell How the absence of Bcl-2 impacts an organism during development The effect of Bcl-2 on tumorigenesis

  13. Chromosomal translocation of the Bcl-2 causes B-cell lymphoma. http://www2.umdnj.edu/pathpweb/new_page_1.htm

  14. Bcl-2 becomes linked an active immunoglobulin promoter, stimulating its overexpression in B-lymphoid tumors. Duronio, R. Feb. 20, 2007

  15. Transgenic mice with the Bcl-2 transgene, Myc transgene, and a combination of both demonstrated their respective roles in cancer initiation. Weinberg, R.A. Figure 9.22A

  16. Excess Myc and Bcl-2 combined caused mutant mice to die from lymphomas at a high rate. Weinberg, R.A. Figure 9.22B

  17. Summary of Bcl-2 Properties 1. Inhibits apoptosis and associates with outer mitochondrial membrane. 2. Internal organs of Bcl-2 knockout mice are ravaged by apoptosis. 3. Bcl-2 is overexpressed in B-cell lymphomas by chromosomal translocation

  18. References Cory, S., Adams, J.M. The Bcl-2 Family: Regulators of the Cellular Life-or-Death Switch. Nature 2, 647-656. (2002) Kamada, S. et al. Bcl-2 deficiency in mice leads to pleiotropic abnormalities: accelerated lymphoid cell death in thymus and spleen, polycystic kidney, hair hypopigmentation, and distorted small intestine. Cancer Research 55, 354-359. (1995) Veis DJ, Sorenson CM, Shutter JR, Korsmeyer SJ. Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair.Cell 75, 229-240. (1993) Weinberg, Robert A. The Biology of Cancer. New York: Garland Science, 2007. Weissman, D. “Pathology Lectures and Case Conferences.” Jul. 2005. UMDNJ - Robert Wood Johnson Medical School. 25 Feb. 2007. <http://www2.umdnj.edu/pathpweb/new_page_1.htm>

  19. Class Handout • The Role of Bcl-2 in Apoptosis and Cancer • 1. Bcl-2 is pro-survival protein that hinders a cell’s entry into apoptosis. • -Bcl-2 homology (BH) domains show the similarities between Bcl-2, BH3-only, and Bax proteins. • -Similar regions explain binding affinity and localization inside the cell. • -Located on the outer mitochondrial membrane and prevents activation of Bak and Bax. • -BH3-only proteins serve to block the function of Bcl-2 and promote entry into apoptosis. • 2. Knockout mice further demonstrate the link between Bcl-2 and apoptosis. • -Bcl-2 mutants undergo massive apoptosis inside certain organs and do not properly execute melanin synthesis (gray mice). • -If even one allele of a primary BH3-only protein is lost as well, the Bcl-2 mutant mouse is rescued. • 3. When Bcl-2 is linked to an immunoglobulin locus via chromosomal translocation, it becomes hyperactive and can produce B-cell lymphomas. • -By ignoring cellular damage and cytotoxic signals, these cancerous B-cells develop into tumors. • -Surplus Bcl-2 combined with an excess of Myc, a promoter of proliferation, causes mice to die at a higher rate than overexpression of either gene.

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