The Role of Bcl-2 in Apoptosis and Cancer Eddie Alcorn.
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Transcript of The Role of Bcl-2 in Apoptosis and Cancer Eddie Alcorn.
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The Role of Bcl-2 in Apoptosis and Cancer
Eddie Alcorn
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Bcl-2 aids in preventing apoptosis.
Hanahan and Weinberg, Cell 100:57-70 (2000)
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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
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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)
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Most cellular Bcl-2 is bound to the outer mitochondrial membrane.
Cory, S., Adams, J.M. Nature 2, 647-656. (2002)
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At the membrane, Bcl-2 blocks Bax and Bak activity.
Cory, S., Adams, J.M. Nature 2, 647-656. (2002)
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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)
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Bax and Bak release Cytochrome C and Diablo from the mitochondria to
induce apoptosis.
Cory, S., Adams, J.M. Nature 2, 647-656. (2002)
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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
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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
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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
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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
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Chromosomal translocation of the Bcl-2 causes B-cell lymphoma.
http://www2.umdnj.edu/pathpweb/new_page_1.htm
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Bcl-2 becomes linked an active immunoglobulin promoter, stimulating its
overexpression in B-lymphoid tumors.
Duronio, R. Feb. 20, 2007
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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
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Excess Myc and Bcl-2 combined caused mutant mice to die from lymphomas at a
high rate.
Weinberg, R.A. Figure 9.22B
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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
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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>
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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.