Block 3 Lecture 5 -- Growth Factors and Oncogenes Flashcards
What mechanisms activate proto-oncogenes to oncogenes?
1) point mutations/deletions in coding sequences
2) point mutations/deletion is regulatory sequences
3) chromosomal translocation
4) insertional mutagenesis
5) gene amplification
What results from a point mutation/deletion in a coding sequence?
structural and functional changes
What results from a point mutation/deletion in a regulatory sequence?
over-expression of protein
What results from a chromosomal translocation?
fusion proteins with novel function
What results from insertional mutagenesis?
aberrant protein expression
Describe the structure of EGFR.
receptor TK
3 domains
– extracellular, transmembrane, cytoplasmic
– not all respond to extracellular ligand
– not all have cytoplasmic tail
How is intracellular signaling initiated from EGFR?
1) receptors dimerize
2) autophosphorylation
3) multiple signaling cascades
What are the 2 main signaling cascades from EGFR?
Ras/Map Kinase
Src/Stat
What is Ras?
a GTPase inactivated in the GDP-bound state
How is Ras a major oncogene?
mutations causing decreased hydrolysis increases Ras activity
What is Src?
a kinase inactivated in its phosphorylated form
What are Src’s domains?
1) kinase
2) Tyr
3) Sh3
4) Sh2
How does phosphorylation of Src inactivate it?
Tyr-PO4 folds up to bind SH2, blocks kinase domain
What is BCR-ABL?
a fusion protein from Philadelphia chromosome
What are the domains of Abl?
1) kinase
2) DNA-binding
3) actin-binding
4) Sh2
5) Sh3
What are the domains of Bcr?
1) Domain I (Tyr-P containing)
2) Domain II
What is the MoA of Gleevec?
blocks kinase domain of Abl
What is the MoA of Nexafar?
inhibit Raf
What is the MoA of Iressa?
blocks active site of EGFR
What is the MoA of Tarceva?
blocks active site of EGFR
What is the MoA of Herceptin and Erbitux?
block EGFR/HER dimerization and ligand binding
What is another therapeutic target of EGFR signaling?
block RAS (keep in GDP state)
