Download The Role of Bcl-2 in Apoptosis and Cancer

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 Connection
between Cancer and
Bcl-2 Overexpression
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
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 Connection
between Cancer and
Bcl-2 Overexpression
The effect of Bcl-2 on tumorigenesis
In a Bcl-2 knockout mouse,
Kamada, S et al.
Figure 2A
• neonatal kidney and immune system are
destroyed by cell suicide.
• Melanocytes are driven to enter apoptosis,
eventually yielding grey mice.
Experiments have shown that a Bcl-2
knockout mouse can be rescued by loss
of a single allele in a BH3-only protein.
BH3-only +/+ and Bcl2 -/=> Apoptosis
BH3-only +/- and Bcl2 -/=> Rescue
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 Connection
between Cancer and
Bcl-2 Overexpression
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
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 with
outer mitochondrial membrane.
2. Internal organs of Bcl-2 knockout
mice are ravaged by apoptosis.
The Connection
between Cancer and
Bcl-2 Overexpression
3. Bcl-2 is overexpressed in B-cell
lymphomas by chromosomal translocation
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-2deficient 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>
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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.