L2, Cancer Genetics I (Oncogenes) Flashcards
G1/S transition in normal vs cancerous cells: Requirements
- Specific requirements to enter S-phase (E-C sources; GFs from outside cell attach to GF rec.s)
- Typically, only a very small percentages of cells will be undergoing this at a given time
- Cancer cells can become self-sufficient in their growth signalling; may produce their own GFs or overexpress GF receptors, constitutive activation downstream in pathway etc
Basic characteristics of oncogenes:
- Presence results in a cancerous phenotype
- Dominant at cellular genetic level
- Derive from genes normally involved in regulating proliferation and survival through either mutation or misregulation
Mechanisms for oncogene activation:
- Deletion or point mutation in coding sequence -> hyperactive protein
- Regulatory mutation -> overproduction of normal protein
- Gene amplification -> overproduction of normal protein
- Chromosome rearrangement -> fusion protein or overexpression
Protooncogenic growth regulatory genes: Broad groups
- Growth Factors
- Growth Factor receptors (e.g. RTKs)
- G proteins
- I-C serine/threonine kinases
- I-C tyrosine kinases
- TFs
- Negative regulators of apoptosis (e.g. Bcl)
Autocrine signalling in cancer: Describe oncogenic process and give two examples with their cancer type
- Example of mutation at the growth factor level
- Normally a cells never produces both the GF and GFR (endocrine or paracrine)
- Cancerous cells can produce their own, bypassing requirement for external GFs
- e.g. PDGF in glioblastomas
- e.g. TGFa in sarcomas
Key example: Proto-oncogenic GF
TGF-alpha
- Ligand of epidermal growth factor receptor (EGF)
- Produced by lung, prostate, pancreatic, mesothelioma and breast cancers
How may GFRs act as oncogenes? (Mechanistic overview)
Deregulated receptor firing…
- Mutations affecting structure
- Overexpression -> molecular crowding -> independent ligand firing
- Dimerisation without ligand (e.g. loss of E-C domains)
Key example: GFRs as oncogenes
- Erb2/HER2/Neu
- Overexpressed in 30% of breast cancers
- Main ligand: NRG, EGF
- Type of receptor tyrosine kinase
- Alteration causes overexpression
Ras overview:
- G-protein: activates by binding GTP, ‘cyclic’ mechanism
- Regulated by GEFs (e.g. SOS) and GAPs (e.g. NF1)
- Humans have 3 genes encoding 4x21kDa Ras proteins, which are involved in various cancer types
- HRAS
- NRAS
- KRAS4A
- KRAS4B
How do Ras proteins become oncogenic?
- Miscoded in various cancer types
- Adaptor proteins link RTK firing to RAS
- KRAS mutations are most common overall
- pstn 12 is a big hotspot for mutation across tumours -> mutational hotspots of Ras correlate with decreased GTPase activity; allowing binding of GTP but not hydrolysis -> constituent activation -> abnormal proliferation downstream
How does bcr-abl become oncogenic?
- Translocation between chromosome 9 and 22 -> Philadelphia Chromosome, bcr-abl oncogene
- Fusion protein -> constitutively active tyrosine kinase
- Found in 95% of CML
What is the function of Myc transcription factor?
Regulates expression of genes involved in promoting cell proliferation and survival
How can Myc become oncogenic? (2 ways)
- myc locus amplified frequently in various leukaemias and carcinomas (10-50%)
- Expression of myc is also deregulated in Burkitt’s lymphoma by chromosomal translocation
ras, EGFR, B-raf, myc, bcr-abl, HER2 -> Sort by mechanism of oncogene activation:
- Deletion/point mutation: ras, B-raf
- Gene amplification: EGFR, HER2, myc
- Chromosome rearrangement (near to a regulatory seq): myc in BL
- Chromosome rearrangement (forming a hyperactive fusion protein): bcr-abl
Give 3 further examples of proto-oncogenic GFs and their receptors:
- SCF (Kit)
- VEGF-A (VEGF-R)
- HGF (Met)
