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Bcl-2: A Matter of Life-or-Death

Bcl-2: A Matter of Life-or-Death. Sarah Greenblatt Biology 169. Overview:. Importance of Apoptosis Apoptosis pathway: C. elegans What is the normal biological role of Bcl-2? How does Bcl-2 contribute to cancer?. Importance of Apoptosis. Embryonic and fetal development

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Bcl-2: A Matter of Life-or-Death

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  1. Bcl-2: A Matter of Life-or-Death Sarah Greenblatt Biology 169

  2. Overview: • Importance of Apoptosis • Apoptosis pathway: C. elegans • What is the normal biological role of Bcl-2? • How does Bcl-2 contribute to cancer?

  3. Importance of Apoptosis • Embryonic and fetal development • Tissue homeostasis • Immune response Alberts el al. Fig. 17-35

  4. What triggers apoptosis? • DNA damage • Detachment from cells/tissues • Growth factor deprivation • Radiation Alberts Fig. 17-37

  5. Model for apoptosis: C. elegans • Lineage of all somatic cells known • 131 cells undergo programmed cell death • CED-1 mutants Ellis and Horvitz. 1986, Cell 91:818

  6. Three major genes involved in apoptosis in C. elegans: • ced-3 – required for apoptosis • ced-4 –required for apoptosis • ced-9 -inhibits apoptosis

  7. t(14;18) places the Bcl-2 gene close to the enhancer for the antibody heavy chain B-cell Lymphoma http://users.rcn.com/jkimball.ma.untranet/BiologyPages

  8. Translocation causes overexpression of Bcl-2 • B cell function: synthesize large amounts of antibody • Enhancer is very active! • Result: Over expression of bcl-2 protein Alberts 24-32

  9. Bcl-2 is mammalian homologue of CED-9 D.L Vaux and S.J Korsemeyer, 1999, cell 96:245

  10. What does it encode? • Integral membrane protein, localized to: • E.R • nuclear envelope • mitochondrial membrane

  11. Bcl-2 Family Gross et al. Bcl-2 family members and the mitochondria in apoptosis. Genes Dev.(1999)

  12. How does Bcl-2 repress apoptosis?

  13. Intrinsic pathway (damage): Mitochondria Cytochrome c release BCL-2 BCL-XL BCL-W Pro-caspase 9 cleavage Apaf1 Pro-execution caspase (3) cleavage Caspase (3) cleavage of cellular proteins, Nuclease activation, Etc. Death

  14. What is the role of the bcl-2 family in normal cells? (Bax, Bak) (Bcl-2, Bcl-xL)

  15. Bcl-2 knockout mice • Growth retardation • Kidney disease • Massive apoptosis in thymus and spleen • Premature grey hair 5 Weeks 10 Weeks • Veis, D.J et al. Cell 75, 229-240 (1993)

  16. How does repression of apoptosis contribute to cancer?

  17. Cellular advantage: resistance to apoptosis: • Cells survive in harsh conditions • Continue to proliferate when DNA damaged • Metastasis • Increased resistance to chemotherapy and radiation

  18. Summary: • Bcl-2 is an oncogene • Over-expressed in a • wide variety of tumors • Bcl-2 protein represses apoptosis Evasion of apoptosis is a critical step in carcinogenesis!

  19. References: • Adams, J. M and Cory, S. The Bcl-2 protein family: arbitrators of cell survival. Science 281,1322-1326 (1998) • Cory, S., Adams, J.M. The Bcl2 family: regulators of the life or death switch. Nature Reviews 2, 647-656 (2002) • Gross, A. McDonnell, J.M. and Korsmeyer, S.J. Bcl-2 family members and the mitochondria in apoptosis. Genes Dev. 13, 1899-1911(1999) • D. Heiser et al. The Bcl-2 family and its role in the development of neoplastic disease. Experimental Gerontology 39(2004) 1125-1135 • Veis, D.J et al. Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic and hypopigmented hair. Cell 75, 229-240 (1993)

  20. http://mcb.berkeley.edu/courses/mcb230/jk_pdfs/16_hengartner_nat00.pdfhttp://mcb.berkeley.edu/courses/mcb230/jk_pdfs/16_hengartner_nat00.pdf

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