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Bcl-2: The Guardian of Cellular Destiny

Delve into the intricate world of Bcl-2 protein and its critical role in determining life or death decisions within cells. Explore how this protein impacts apoptosis, contributes to cancer development, and regulates various biological processes like embryonic development and immune responses. Unravel the mechanisms through which Bcl-2 represses apoptosis and understand the repercussions of its dysregulation in diseases like cancer. Discover the significance of the Bcl-2 family in maintaining cell health and the consequences of its malfunction.

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Bcl-2: The Guardian of Cellular Destiny

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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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