The Role of Bcl-2 in Apoptosis and Cancer

Eddie Alcorn

Bcl-2 aids in preventing apoptosis.

Hanahan and Weinberg, Cell 100:57-70 (2000)

Table of Contents

How Bcl-2 Functions Biochemically in a Normal Cell

The Biological Role of Bcl-2 Protein

The cell machinery and jobs of Bcl-2 in a typical cell

How the absence of Bcl-2 impacts an organism during development

The effect of Bcl-2 on tumorigenesisThe Connection

between Cancer and Bcl-2 Overexpression

Bcl2 is part of a family of related proteins that play different roles in

apoptosis.

Cory, S., Adams, J.M. Nature 2, 647-656. (2002)

Most cellular Bcl-2 is bound to the outer mitochondrial membrane.

Cory, S., Adams, J.M. Nature 2, 647-656. (2002)

At the membrane, Bcl-2 blocks Bax and Bak activity.

Cory, S., Adams, J.M. Nature 2, 647-656. (2002)

BH3-only protein binds and inhibits Bcl-2, discontinuing its obstruction to Bax and

Bak activity.

Cory, S., Adams, J.M. Nature 2, 647-656. (2002)

Bax and Bak release Cytochrome C and Diablo from the mitochondria to

induce apoptosis.

Cory, S., Adams, J.M. Nature 2, 647-656. (2002)

Table of Contents

How Bcl-2 Functions Biochemically in a Normal Cell

The Biological Role of Bcl-2 Protein

The cell machinery and jobs of Bcl-2 in a typical cell

How the absence of Bcl-2 impacts an organism during development

The effect of Bcl-2 on tumorigenesis

The Connection between Cancer and Bcl-2 Overexpression

In a Bcl-2 knockout mouse,

• neonatal kidney and immune system are destroyed by cell suicide.

• Melanocytes are driven to enter apoptosis, eventually yielding grey mice.

Kamada, S et al. Figure 2A

Experiments have shown that a Bcl-2 knockout mouse can be rescued by loss of a single allele in a BH3-only protein.

Cory, S., Adams, J.M. Nature 2, 647-656. (2002)

BH3-only +/+ and Bcl2 -/-=> Apoptosis

BH3-only +/- and Bcl2 -/-=> Rescue

Table of Contents

How Bcl-2 Functions Biochemically in a Normal Cell

The Biological Role of Bcl-2 Protein

The cell machinery and jobs of Bcl-2 in a typical cell

How the absence of Bcl-2 impactsan organism during development

The effect of Bcl-2 on tumorigenesis

The Connection between Cancer and Bcl-2 Overexpression

Chromosomal translocation of the Bcl-2 causes B-cell lymphoma.

http://www2.umdnj.edu/pathpweb/new_page_1.htm

Bcl-2 becomes linked an active immunoglobulin promoter, stimulating its

overexpression in B-lymphoid tumors.

Duronio, R. Feb. 20, 2007

Transgenic mice with the Bcl-2 transgene, Myc transgene, and a combination of both demonstrated

their respective roles in cancer initiation.

Weinberg, R.A. Figure 9.22A

Excess Myc and Bcl-2 combined caused mutant mice to die from lymphomas at a

high rate.

Weinberg, R.A. Figure 9.22B

Summary of Bcl-2 Properties

How Bcl-2 Functions Biochemically in a Normal Cell

The Biological Role of Bcl-2 Protein

1. Inhibits apoptosis and associates withouter mitochondrial membrane.

2. Internal organs of Bcl-2 knockout mice are ravaged by apoptosis.

3. Bcl-2 is overexpressed in B-cell lymphomas by chromosomal translocation

The Connection between Cancer and Bcl-2 Overexpression

References

Cory, S., Adams, J.M. The Bcl-2 Family: Regulators of the Cellular Life-or-Death Switch. Nature 2, 647-656. (2002)

Kamada, S. et al. Bcl-2 deficiency in mice leads to pleiotropic abnormalities: accelerated lymphoid cell death in thymus and spleen, polycystic kidney, hair hypopigmentation, and distorted small intestine. Cancer Research 55, 354-359. (1995)

Veis DJ, Sorenson CM, Shutter JR, Korsmeyer SJ. Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair.Cell 75, 229-240. (1993)

Weinberg, Robert A. The Biology of Cancer. New York: Garland Science, 2007.

Weissman, D. “Pathology Lectures and Case Conferences.” Jul. 2005. UMDNJ - Robert Wood Johnson Medical School. 25 Feb. 2007. <http://www2.umdnj.edu/pathpweb/new_page_1.htm>

Class Handout• The Role of Bcl-2 in Apoptosis and Cancer• 1. Bcl-2 is pro-survival protein that hinders a cell’s entry into apoptosis.• -Bcl-2 homology (BH) domains show the similarities between Bcl-2, BH3-only, and

Bax proteins.• -Similar regions explain binding affinity and localization inside the cell.• -Located on the outer mitochondrial membrane and prevents activation of Bak and Bax.• -BH3-only proteins serve to block the function of Bcl-2 and promote entry into

apoptosis.• 2. Knockout mice further demonstrate the link between Bcl-2 and apoptosis.• -Bcl-2 mutants undergo massive apoptosis inside certain organs and do not properly

execute melanin synthesis (gray mice).• -If even one allele of a primary BH3-only protein is lost as well, the Bcl-2 mutant

mouse is rescued.• 3. When Bcl-2 is linked to an immunoglobulin locus via chromosomal translocation, it becomes

hyperactive and can produce B-cell lymphomas.• -By ignoring cellular damage and cytotoxic signals, these cancerous B-cells develop

into tumors.• -Surplus Bcl-2 combined with an excess of Myc, a promoter of proliferation, causes

mice to die at a higher rate than overexpression of either gene.