Extracellular Regulation of Apoptosis

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Extracellular Regulation of Apoptosis
Fas Ligand
Positive Regulation
Activated Fas receptor activates Apaf
2
Negative Extracellular Regulation of Apoptosis
Survival Factors Secreted from neighboring
cells. Inhibit activation of apoptosis
pathway. Mechanism of action not clear.
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Growth Factors
Apaf
p53
Apaf
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Cancer
Loss of control of cell division

• Caused by mutations in genes that code for
  proteins involved in

• Cell cycle regulation
• Apoptosis regulation
• DNA repair

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Clonal Evolution of Tumors
multi-hit hypothesis
apc- apc-
Spreads to other tissues (metastasize)
apc- ras apc- ras

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Mutations in two general categories of genes lead
to tumor formation
Oncogenes Dominant mutations
Overproduction of protein product
Hyperactive protein Proto-oncogene normal form
of oncogene. Tumor Suppressor genes Recessive
mutations Loss of protein product
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Classes of Oncogenes
Mitogens (Growth Factors) Mitogen Receptors
(RTKs) Intracellular signal transducers e.g.,
G-proteins, Kinases Transcription
Factors Apoptosis Inhibitors
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Types of Oncogene Mutations
Point Mutations (single amino acid changes)
GTP-binding pocket of Ras protein
Mutant protein has decreased GTPase activity
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Deletion of a protein domain (needed for negative
allosteric regulation)
Active even when not bound by ligand
C-terminus
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Gene Fusions
exon 1
Translocation
Philadelphia chromosome Found in many cases of
CML. (chronic myelogenous leukemia)
c-abl exon 1 encodes N-terminal negative
regulatory domain. Bcr-Abl fusion protein has Abl
kinase activity, but lacks regulatory domain.