Download Bcl-2: Regulator of the Cellular Life-or

Bcl-2: A Matter of Life-or-Death
Sarah Greenblatt
Biology 169
Overview:
• Importance of Apoptosis
• Apoptosis pathway: C. elegans
• What is the normal biological role of
Bcl-2?
• How does Bcl-2 contribute to cancer?
Importance of Apoptosis
• Embryonic and fetal development
• Tissue homeostasis
• Immune response
Alberts el al. Fig. 17-35
What triggers apoptosis?
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DNA damage
Detachment from cells/tissues
Growth factor deprivation
Radiation
Alberts Fig. 17-37
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 91:818
Three major genes involved in
apoptosis in C. elegans:
• ced-3 – required for apoptosis
• ced-4 –required for apoptosis
• ced-9 -inhibits apoptosis
B-cell Lymphoma
• t(14;18) places the Bcl-2 gene close to the
enhancer for the antibody heavy chain
http://users.rcn.com/jkimball.ma.untranet/BiologyPages
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
Bcl-2 is mammalian homologue of
CED-9
D.L Vaux and S.J Korsemeyer, 1999, cell 96:245
What does it encode?
• Integral membrane protein, localized
to:
• E.R
• nuclear envelope
• mitochondrial membrane
Bcl-2 Family
Gross et al. Bcl-2 family members and the mitochondria in apoptosis. Genes Dev.(1999)
• How does Bcl-2 repress apoptosis?
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
What is the role of the bcl-2 family
in normal cells?
(Bax, Bak)
(Bcl-2, Bcl-xL)
Bcl-2 knockout mice
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Growth retardation
Kidney disease
Massive apoptosis in thymus and spleen
Premature grey hair
5 Weeks
•Veis, D.J et al. Cell 75, 229-240 (1993)
10 Weeks
How does repression of apoptosis
contribute to cancer?
Cellular advantage: resistance to
apoptosis:
• Cells survive in harsh conditions
• Continue to proliferate when DNA
damaged
• Metastasis
• Increased resistance to chemotherapy
and radiation
Summary:
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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!
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) 11251135
• Veis, D.J et al. Bcl-2-deficient mice demonstrate fulminant
lymphoid apoptosis, polycystic and hypopigmented hair. Cell
75, 229-240 (1993)
http://mcb.berkeley.edu/courses/mcb230/jk_pdfs/16_hengartner_nat00.pdf