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 • Tissue homeostasis• Immune response

Alberts el al. Fig. 17-35

What triggers apoptosis?

• DNA damage• Detachment from cells/tissues • Growth factor deprivation• Radiation

Alberts Fig. 17-37

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

Three major genes involved in apoptosis in C. elegans:

• ced-3 – required for apoptosis• ced-4 –required for apoptosis• ced-9 -inhibits apoptosis

• 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

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

Bcl-2 is mammalian homologue of CED-9

D.L Vaux and S.J Korsemeyer, 1999, cell 96:245

What does it encode?

• Integral membrane protein, localized to:• E.R

• nuclear envelope

• mitochondrial membrane

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

Bcl-2 Family

• How does Bcl-2 repress apoptosis?

Apaf1

Intrinsic pathway (damage):

Mitochondria

Cytochrome c release

Pro-caspase 9 cleavage

Pro-execution caspase (3) cleavage

Caspase (3) cleavage of cellular proteins,Nuclease activation,

Etc.

Death

BCL-2BCL-XLBCL-W

What is the role of the bcl-2 family in normal cells?

(Bcl-2, Bcl-xL)(Bax, Bak)

Bcl-2 knockout mice• Growth retardation• Kidney disease• Massive apoptosis in thymus and spleen• Premature grey hair

•Veis, D.J et al. Cell 75, 229-240 (1993)

5 Weeks 10 Weeks

How does repression of apoptosis contribute to cancer?

Cellular advantage: resistance to apoptosis:

• Cells survive in harsh conditions• Continue to proliferate when DNA

damaged• Metastasis• Increased resistance to chemotherapy

and radiation

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!

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)

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