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
What family do the MYC oncoproteins belong to?
→family of transcription factors
What are the major downstream effectors of MYC?
→ribosome biogenesis,
→protein translation,
→cell-cycle progression
→metabolism
What virus was MYC proteins first identified in?
→avian myelocytomatosis virus
What does MYC encode?
→helix-loop-helix leucine zipper transcription factor
What does the helix loop helix zipper dimerise with?
→Max, to transactivate gene expression
What can be the result of deregulation of MYC?
→chromosomal translocation
What lymphoma is EBV associated with?
→Burkitt’s lymphoma
Describe Burkitt’s lymphoma
→BL is a high grade lymphoma
→can effect children from the age of 2 to 16 years
What do all cases of Burkitt’s lymphoma carry?
→chromosomal translocations that place the MYC gene under the regulation of the Ig heavy chain
→c-myc expression is deregulated
What is classical African or endemic BL?
→children with chronic malaria infections have a reduced resistance to the virus
What are the three distinct alternative chromosomal translocations and what do they fuse with?
→chromosome 2,14,22
→form one of these three chromosomes is fused to a section of chromosome 8
WHat percentage of chronic myelogenous leukaemia carry Philadelphia?
→95%
What fusion does Philadelphia chromosomes involve?
→BCR-ABL fusion protein
→tyrosine kinase activity
of the oncogene ABL is constitutive
What is inhibited in Imainib therapy for CML?
→tyrosine kinase inhibitor
What are some intrinsic tumour suppressor pathways?
→RB
→p53
→TAp73
What does loss of tumour suppressor gene function require?
→requires inactivation of both alleles of the gene
→recessive genes
What are three functions of suppressor genes?
→regulators of cell cycle checkpoints (e.g. RB1),
→differentiation (e.g. APC)
→DNA repair (e.g. BRCA1)
Why does retinoblastoma occur?
→immature retinoblasts continue to grow very fast and do not turn into
mature retinal cells.
What is characteristic about a retinoblastoma eye?
→reflect light back in a white colour
What are the two forms of retinoblastoma?
→familial (40%) and sporadic (60%)
Which chromosome is affected in retinoblastoma?
→on chromosome 13 (13q14),
the retinoblastoma 1 (Rb1) gene along with BRCA2
What is the retinoblastoma two-hit hypothesis?
→the loss of both of the functional copies of the Rb gen
What are the Rb proteins known as?
→pocket proteins
What does RB mainly bind to?
→E2F transcription factor
What is the function of the G1 checkpoint?
→leads to the arrest of the cell cycle in response to DNA damage
What is a substrate of RB in the cell cycle?
→cyclin D
WHat is RB phosphorylated by?
→Cyclin D and E families and their cdk
What happens when RB is hyperphosphorylated?
→becomes inactive
→E2F is released and migrates to the nucleus to induce transcription
→progression from G1 to S occurs
Which three viruses have been found to destabilise Rb?
→Adenovirus - E1A
→Papilloma - E7
→Polyoma – Large T antigen
Describe p53 structure?
→an amino transactivation domain,
→a central DNA binding domain,
→a tetramerization domain
→a carboxyl regulatory domain
How are p53 levels kept low?
→by MDM2 protein
What is the MDM2 protein function?
→a ubiquitin ligase (also an oncogene)-
→targets for proteosome for degradation
How does MDM target p53 for proteasome?
→MDM2 binds p535 to form a complex in the nucleus
→ modifies the carboxyl terminus of p53 MDM modifies the carboxyl terminus of p53
What is the half life of p53?
→20 min half life
What does phosphorylation of p53 lead to?
→disrupts the interaction between it and
MDM2
What does PRIMA-1 do to muatant p53?
→ Restores mutant p53 by modifying the thiol groups in the core domain of the protein
What is nutilin?
→a potent MDM2 antagonist
How is RITA a p53 therapeutic?
→binds to p53
→increases half life of p53,
→prevents export of p53 to proteosome
What does inhibition of CRM1 lead to?
→nuclear
accumulation of p53
