BCL-2

Sarah A. Norris

APOPTOSIS

Programmed cell death

http://virtuallaboratory.net/Biofundamentals/lectureNotes/Topic5-4_CellDeath.htm

http://upload.wikimedia.org/wikipedia/commons/8/8a/Bcl-2_Family.jpg

BCL-2 STRUCTURE

Encodes an integral membrane protein.

Localized to outer membranes of mitochondria, endoplasmic reticulum, and nuclear envelope. Targeted by 21 C-terminal hydrophobic amino

acids

STRUCTURE

Globular bundle of 5 amphipathic α-helices surround 2 central hydrophobic α-helices

Hydrophobic groove formed by BH1, BH2, BH3

http://opm.phar.umich.edu/images/proteins/1g5m.gif, (Fesik 2005)

APOPTOSIS: THE STRESS PATHWAYCell damage

mitochondrialdamage

Mitochondria

Cytochrome -c

Procaspase 9APAF 1

Caspases3, 6, 7

Caspase 9

Apoptosome

BCL-2

(Ashkenazi 2002)

HOW DOES BCL-2 INHIBIT APOPTOSIS?

1. Binds Apaf-1, inhibiting Caspase-9 binding

HOW DOES BCL-2 INHIBIT APOPTOSIS?

2. Prevents release of cytochrome c from mitochondria

DIMERIZATION

activation deactivation

deactivation(competitive inhibition)

Bad

http://www.bentham.org/cmm/sample/cmm1-1/Kornbluth/Kornbluth-fig4-pg97.jpg

BIOLOGICAL ROLE

BIOLOGICAL ROLE

(Lewis 2000)

Homozygous null mutant

http://www.informatics.jax.org/javawi2/servlet/WIFetch?page=markerDetail&key=529

BCL-2: DISCOVERY

Human proto-oncogene

Discovered in t(14;18) translocations in B-Cell Lymphomas and leukemias.

CANCER

(Tsujimoto 1984)

CANCER

Overexpression contributes to tumorigenesis by inhibiting apoptosis

Mutations are implicated in melanoma, breast, prostate, and lung carcinomas

Facilitates metastasis

Dampens response to chemotherapy and radiation

TREATMENT

Down-regulation can increase chemosensitivity

Genasense – an antisense oligonucleotide drug

REFERENCES Ashkenazi A. Targeting death and decoy receptors of the tumour-necrosis factor

superfamily. Nat Rev Cancer, 2, 420–430 (2002). Cleary ML, Smith SD, et. al. Cloning and structural analysis of cDNAs for bcl-2 and a

hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation. Cell, 47, 19-28 (1986).

Cory S, Adams J. The Bcl2 Family: Regulators of the cellular life-or death switch. Nat Rev Cancer, 2, 647-656 (2002).

Fesik SW, Promoting apoptosis as a strategy for cancer drug discovery. Nat Rev Cancer, 5, 876-885 (2005).

Haldar S, Beatty C, et. al. The bcl-2 gene encodes a novel G protein. Nature 342, 195 - 198 (1989).

Horvitz HR. Genetic control of programmed cell death in the nematode Caenorhabditis elegans. Cancer Res. 59, S1701–S1706 (1999).

Lewis K. Programmed death in bacteria. Microbiol Mol Biol Rev 64, 503-514 (2000). Reed JC, Tsujimoto Y, et. Al. Regulation of bcl-2 Proto-Oncogene Expression During

Normal Human Lymphocyte Proliferation. Science, 236, 1295-1299 (1987). Tsujimoto Y. Cloning of the Chromosome Breakpoint of Neoplastic B Cells with the

t(14;18) Chromosome Translocation. Science, 226, (1984). Vaux DL. Weissman, I. L. & Kim, S. K. Prevention of programmed cell death in

Caenorhabditis elegans by human BCL-2. Science 258, 1955–1957 (1992).