Extracellular Regulation of Apoptosis Fas Ligand Positive Regulation Activated Fas receptor activates Apaf

Negative Extracellular Regulation of Apoptosis Survival Factors: Secreted from neighboring cells. Inhibit activation of apoptosis pathway. Mechanism of action not clear.

Growth Factors Apaf p53 Apaf

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

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

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

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

(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

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

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.