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

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

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. B-cell Lymphoma
t(14;18) places the Bcl-2 gene close to the enhancer for the antibody heavy chain

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, (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, (1998)
Cory, S., Adams, J.M. The Bcl2 family: regulators of the life or death switch. Nature Reviews 2, (2002)
Gross, A. McDonnell, J.M. and Korsmeyer, S.J. Bcl-2 family members and the mitochondria in apoptosis. Genes Dev. 13, (1999)
D. Heiser et al. The Bcl-2 family and its role in the development of neoplastic disease. Experimental Gerontology 39(2004)
Veis, D.J et al. Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic and hypopigmented hair. Cell 75, (1993)

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