1. 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.

3. Growth Factors
Apaf
p53
Apaf

4. 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

5. Clonal Evolution of Tumors
multi-hit hypothesis
apc-
apc- ras*
apc- ras+
Spreads to other tissues
(metastasize) ;

6. 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

7. Classes of Oncogenes Mitogens (Growth Factors)
Mitogen Receptors (RTKs)
Intracellular signal transducers: e.g., G-proteins, Kinases
Transcription Factors
Apoptosis Inhibitors

8. (single amino acid changes)
Types of Oncogene Mutations
Point Mutations
(single amino acid changes)
GTP-binding pocket of Ras protein
Mutant protein has decreased GTPase activity

9. Deletion of a protein domain
(needed for negative allosteric regulation)
Active even when not bound by ligand
C-terminus

10. 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.