Oncogenes And Tumour Suppressor Genes Flashcards
What are the major functional changes in cancer?
- Increased growth
- Failure to undergo apoptosis or senescence
- Loss of differentiation
- Failure to repair DNA damage
How does increased growth happen in cancer?
Loss of regulation and stimulation of environment promoting growth
What do oncogenes cause?
Oncogenes will normally make cells divide and drive cell division forward, mutations mean that they may be permanently active
- mutation gains function
What are oncogenes?
Altered gene whos product can act in a dominant fashion to help make a cell cancerous
What is the normal version of oncogenes?
Protoconcogenes
What do tumour supressor genes cause?
Tumour suppressors will do the opposite (and may also be involved in cell cycle arrest?) if you have a mutated oncogene, tumour suppressor genes may still be strong enough to stop proliferation
- mutation loses function
Explain why tumour suppressor genes need to undergo two mutations as opposed to oncogenes
Tumour suppressors become oncogenic when they lose function unlike oncogenes that become oncogenic when they gain function.
- TS genes need BOTH alleles (one on each chromosome) to be inactivated in order to cause oncogenesis
What is Rous’s protocol for inducing sarcoma in chickens?
- Remove sarcoma and break up into small tissue chunks
- Grind up with sand
- Filter and collect filtrate through a fine-pore filter
- Inject filtrate into young chickens
- Observe sarcoma in injected chickens
Name the extra gene found in Rous sarcoma virus
V-SRC
What is this gene (V-SRC)?
- V-SRC (viral SRC) is a mutated cellular gene, so in uninfected chickens there was found to be a SRC homologue that was not pathogenic.
- So some genes from cancer causing viruses are mutated forms of cellular genes that have been ‘kidnapped’ by the virus
- C-SRC is usually involved in the positive regulation of cell growth and division
How can this ‘kidnapping’ happen?
- Retroviruses convert their RNA into DNA by reverse transcriptase and then integrate this into the host genome - in one of the viruses, this integration was accidentally next to C-SRC (cellular SRC) and then there is co-transcription of the viral DNA AND C-SRC - this is then packaged into the capsid and the new RSV produced has C-SRC in it
So explain how RSV infection can lead to oncogenesis
V-SRC is expressed at high levels in the host cell leading to uncontrolled host cell growth → cancer
- I am not sure if there is an actual mutation in V-SRC or if it is the same as C-SRC but just expressed more
Discuss a different mechanism for viral oncogenesis
Viral oncogenes also exist (so not genes that have come from a host originally), these can be in DNA or RNA viruses
- DNA viruses encode various proteins and along with environmental factors can initiate and maintain tumours
- RNA viruses integrate DNA copies of their genomes into the genome of the host cell and as these contain transforming oncogenes they induce cancerous transformation of the host
What is the capture of c-src by retrovirus?
During evolution, the virus can acquire fragments of genes from the host at integration sites and this process results in the creation of oncogenes
What is the c-src oncogene product?
60 kDa intracellular tyrosine kinase
What can the C-Src oncogene do?
Phosphorylate cellular proteins and affect growth
Name 3 ways that mutations in a proto-oncogene can cause it to become an oncogene
- translocation or transportation to a new promoter
- gene amplification so multiple copies of the gene
- point mutation within the gene causing it to become resistant to degradation or hyperactive
What do gene duplications/amplifications do for oncogenes?
Increase synthesis of encoded proteins
Name the 4 types of proteins that are normally involved in the transduction of growth signals to a cell so different protein types encoded by proto-oncogenes
- Growth factors
- Growth factor receptors
- Intracellular signal transducers
- Nuclear transcription factors
What is the name of the pathway that RAS and RAF activate?
- ERK MAP kinase pathway
- Ictivated by growth factor receptors and leads to the induction of additional genes such as fos that encode potentially oncogenic proteins (so for proliferation)
What do the majority of oncogene proteins function as?
Elements of the signalling pathways that regulate cell proliferation and surivival in response to growth factor stimulation
Describe the RAS oncogene family - what are RAS proteins, what do they do?
- RAS proteins are small GTPases that are normally bound to GDP in a neutral state
- Is a signal transducer in proliferation, making it an oncogene
RAS is activated in one third of all cancers - this makes it the most commonly mutated oncogene
What do the majority of oncogene proteins function as?
Growth factors, growth backer receptors and intracellular signalling molecules
What were RAS oncogenes identified from?
Studies of two cancer causing cell lines
What proportion of oncogenic activation of RAS is seen in human cancer?
RAS is activated in one third of all cancers - this makes it the most commonly mutated oncogene
What codons are the mutations in on RAS oncogenes?
12, 13 and 61
Glycine → Valine = bladder carcinoma
Glycine → Cysteine = lung cancer
What do the point mutations lead to in RAS oncogenes?
Loss of GTPase acting on the RAS protein that is normally used to inactivate the RAS GDP
How do the RAS oncogene intracellular signal transducers work?
Binding of extracellular growth factor signal
→ Promotes recruitment of RAS proteins to the receptor complex
→ recruitment promotes RAS to exchange GDP for GTP (activates RAS)
→ activated RAS then initiates the remainder of the signalling cascade (mitogen activated protein kinases)
→ kinases ultimately phosphorylate targets such as transcription factor to promote expression of genes important for growth and survival
Name the 3 members of the MYC oncogene family and the protein they encode
- C-MYC → c-Myc
- MYCN → N-Myc
- MYCL → L-Myc
Describe the function of these MYC proteins
They are transcription factors that regulate the transcription of at least 15% of the entire genome
- some of the major effectors include ribosome synthesis, protein translation, metabolism, proliferation … SO they are really important!
- overexpressed in the majority of tumours
Describe how MYC is activated into an oncogene
This is NOT via a mutation, but by chromosomal translocation
- so it is placed downstream of a foreign transcriptional promoter
Where was the MYC oncogene family originally identified?
In avian myelocytomatosis virus
What are MYC oncoproteins?
Transcription factors
What are the 3 chromosomal translocations associated with BL?
Parts of chromosomes 2, 14 and 22 attach themselves to chromosome 8 → lose control of MYC so uncontrolled proliferation
Explain the 2 hit hypothesis, using Rb as an example
- There is familial (hereditary) and sporadic retinoblastoma.
- You need one mutation on each allele for tumour suppressor genes to become non-functional (and therefore cancerous) so we may call them recessive.
- So if you have the inherited mutation, you are much more likely to develop the disease!
- this is why sporadic tumour occurs much later on as both alleles need to be mutated
So what is the function of Rb in this step through G1 - how does it do it?
- Rb protein is a substrate for cyclin D in this step
- Cyclin D and cyclin E and their CDKs phosphorylate Rb
- so phosphorylated Rb can NOT bind (is detached) to E2F, meaning that transcription can occur (as Rb is inhibiting E2F) so the cell can now progress to S phase
- DNA damage would cause de-phosphorylation of Rb so that cell can not progress through G1 checkpoint
Explain why tumour suppressor genes need to undergo two mutations as opposed to oncogenes
Tumour suppressors become oncogenic when they lose function unlike oncogenes that become oncogenic when they gain function.
- TS genes need BOTH alleles (one on each chromosome) to be inactivated in order to cause oncogenesis
