Bcl-2: A Matter of Life-or-Death

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Bcl-2 A Matter of Life-or-Death

• Sarah Greenblatt
• Biology 169

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Overview

• Importance of Apoptosis
• Apoptosis pathway C. elegans
• What is the normal biological role of Bcl-2?
• How does Bcl-2 contribute to cancer?

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Importance of Apoptosis

• Embryonic and fetal development
• Tissue homeostasis
• Immune response

Alberts el al. Fig. 17-35
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What triggers apoptosis?

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

Alberts Fig. 17-37
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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 91818
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Three major genes involved in apoptosis in C.
elegans

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

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B-cell Lymphoma

• t(1418) places the Bcl-2 gene close to the
  enhancer for the antibody heavy chain

http//users.rcn.com/jkimball.ma.untranet/BiologyP
ages
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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
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Bcl-2 is mammalian homologue of CED-9
D.L Vaux and S.J Korsemeyer, 1999, cell 96245
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What does it encode?

• Integral membrane protein, localized to
• E.R
• nuclear envelope
• mitochondrial membrane

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Bcl-2 Family

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

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• How does Bcl-2 repress apoptosis?

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Intrinsic pathway (damage)
Mitochondria
Cytochrome c release
BCL-2 BCL-XL BCL-W
Pro-caspase 9 cleavage
Apaf1
Pro-execution caspase (3) cleavage
Caspase (3) cleavage of cellular
proteins, Nuclease activation, Etc.
Death
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What is the role of the bcl-2 family in normal
cells?
(Bax, Bak)
(Bcl-2, Bcl-xL)
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Bcl-2 knockout mice

• Growth retardation
• Kidney disease
• Massive apoptosis in thymus and spleen
• Premature grey hair

5 Weeks
10 Weeks

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

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How does repression of apoptosis contribute to
cancer?
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Cellular advantage resistance to apoptosis

• Cells survive in harsh conditions
• Continue to proliferate when DNA damaged
• Metastasis
• Increased resistance to chemotherapy and
  radiation

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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!
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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)

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http//mcb.berkeley.edu/courses/mcb230/jk_pdfs/16_
hengartner_nat00.pdf