L22: Oncogenes & Tumour Suppressor Genes Flashcards
What are the major functional changes in cancer?
→increased growth
→failure
→loss of differentiation
→failure to repair DNA damage
What are oncogenes normally components of?
→growth factor signalling pathways that when mutated produce products in higher quantities
What do tumour suppressor gene act as?
→a stop signal to uncontrolled growth, may inhibit the cell cycle or trigger apoptosis
What was the discovery of Rous’ protocol?
→sarcoma was transmissible through viruses-
What was found in Rous’ extra gene?
→there is an extra gene
Explain the oncogene hypothesis
→some genes of cancer causing viruses were mutated forms of the cellular gene not viral genes
→Rous sarcoma viral gene was in fact a host gene that had
been ‘kidnapped’ by the virus (and ‘transformed’ into an oncogene
What is the oncogene characterised by in c-src and how does it exert its effect?
→60kDa intracellular tyrosine kinase
→Can phosphorylate cellular proteins and effect growth
What are some agents that can turn proto-oncogenes to oncogenes?
→Chemicals
→Physical
→Viruses
What percentage of cancers are caused by oncoviruses?
→15-20%
How do DNA viruses exert their cancerous effect?
→cause lytic infection leading to the death of the cellular host
→can replicate their DNA along with that of the
host and promote neoplastic transformation
How do RNA viruses exert their cancerous effect?
→Integrate DNA copies of their genomes into the genome of the host cell →these contain transforming oncogenes they induce cancerous transformation of the host
What are ways oncogenes are activated?
→Mutation
→Amplification/duplication
→Translocation
What are the 4 types of proteins involved in the transduction of growth signals?
→Growth factors
→Growth factor receptors
→Intracellular signal transducers
→Nuclear transcription factors
Where in the cell is Ras and Raf found?
→intracellular
How is Ras and Raf involved in oncogenic transcriptional regulatory proteins?
→ERK MAP kinase pathway
→induction of additional genes
Which studies was ras genes identified in?
→Harvey sarcoma virus
→Kirsten sarcoma virus
What are Ras proteins?
→small GTPases that are normally bound to GDP in a neutral state
What percentage of human cancer involve Ras oncogenic activation?
→30%
What mutations lead to Ras oncogenic activation?
→Point mutations in codons 12, 13 and 61
What is the amino acid change in Ras oncogenic activation leading to bladder carcinoma?
→Glycine to valine
What is the amino acid change in Ras oncogenic activation leading to lung cancer?
→Glycine to cysteine
Describe the transduction pathway of Ras proteins
→Binding of extracellular growth factor signal
- Promotes recruitment of RAS proteins to the receptor complex
- Recruitment promotes Ras to exchange GDP (inactive
Ras) with GTP (active Ras)
4. Activated Ras then initiates the remainder of the signalling cascade (mitogen activated protein kinases)
- These kinases ultimately phosphorylate targets, such as
transcription factor to promote expression of genes
important for growth and survival
Ras hydrolyzes GTP to GDP fairly quickly, turning itself “off”
What does mutation in the RAS protein lead to?
→loss of GTPase activity of the RAS protein
normally required to return active RAS to
the inactive RAS GDP
What are the three members of the MYC oncogene family?
→ C-MYC,
→MYCN,
→MYCL,
→which encode c-Myc, N-Myc, and L-Myc, respectively
