Oncogenes and tumour suppressor genes Flashcards
what are tumour suppressor genes
genes that slow down division, repair DNA mistakes
when mutation occur, loss of function and lead to cancer , both copies need to be mutated to be inactivated
What are the two types of tumour suppressor genes
- gate keeper (Rb)
- to negatively regulate cell growth
- • Encode proteins that inhibit proliferation, induce apoptosis, inhibit angiogenesis or induce cell adhesion - Caretaker
• To maintain chromosomal integrity
• Prevent cell division if DNA is damaged
• Eg. p53 (encoded by TP53)
Cause of Retinoblastoma
40% due to mutation in retinoblastoma gene - affect both eyes
60% unknown (no mutation ) and affect one eye only
Describe the molecular cause of retinoblastoma
- At G1 checkpoint, most important TF needed to start building of proteins for DNA replication is E2F (bound to another protein eg. Retinoblastoma)
* RB binds to transcription factor E2F in order to inactivate it as it keeps the cells at the checkpoint between G1 and S.
* In order for the cell to proceed to S-phase, RB must be hyperphosphorylated to inactivate it.• If retinoblastoma gene is mutated,
• Mutated RB is dysfunctional as it cannot bind to E2F,
• It wont be able to function and E2F TF will move the cell into S-phase
•
What does the twohit knudson hypothesis suggest
The Two hit Knudson hypothesis states that inherited retinoblastoma occurs when one defective RB1 copy is inherited and the other copy acquires a mutation.
In spontaneous, person has two normal copies and require two spontaneous mutation for tumors to arise
Are TSG dominant or recessive
both, for recessive, heterozygotes displays wildtype because one healthy allele is enough to stop the tumour developing
for dominant, if person inherited a mutation allele, greater risk of developing retinoblastoma as one mutation
can be acquired to cause the disease.
What affects the function of p53
loss of nucleotides, radiation (UV, ionising), oncogene signalling, hypoxia (lack of oxygen reaching tissues), inhibition of transcription
how does p53 suppress tumour growth
in response to DNA damage or stress, it activates a gene to stop cell cycle or to trigger apoptosis in damaged cells
Describe the downstream effects of p53
- Cell cycle arrest
• p53 prevents cells with faulty DNA dividing by activating cell cycle checkpoints.
• p53 upregulates p21, which binds to CDK1 or CDK2 to prevent entry into S-phase.
• This can be reversible of irreversible.- DNA repair
• P53 also regulates nucleotide excision repair of DNA
• DNA-damaging agents upregulate p53 expression, which can promote expression of genes involved in DNA repair such as p53R2 and Gadd45
• or interact directly with AP endonuclease and DNA polymerase. - Blocking of angiogenesis
• alterations in expression of genes that can stimulate tumour angiogenesis (consequence of its TF activity) - Apoptosis
• p53 switches on Bax in faulty cells to initiate mitochondrial permeabilisation and apoptosis.
- DNA repair
Describe the regulation of p53
p53 is regulated by Mdm2 E3-ubiquitin. Mdm2 keeps cellular p53 levels low
by binding to its transactivation domain, preventing it from acting as a
transcription factor. Mdm2 also promotes p53 movement into the cytosol
where it can be bound by ubiquitin to be degraded. In damaged cells, kinases
are recruited to phosphorylate p53 to prevent Mdm2 binding and initiate
apoptosis. It can also be regulated by ARF binding to Mdm2 to prevent p53
degradation. p53 is involved in the G1/S as well as the G2/M cell cycle
checkpoints.
What is RSV
- virus shown to cause sarcomas following experiments in chickens.
- RSV transform primary fibroblasts as it carries a tumorigenic factor – gene v-src.
- Transformed cells show the following characteristics:
- Altered plasma membrane (blebbing)
- Altered adherence (rounded and loss of monolayer)
- Altered cell proliferation (high cell density and immortality)
How are oncogenes activated and the 4 mechanisms
• When proto-oncogene mutates or overexpress -> becomes permanently turned on
• Cells grow uncontrollably and lead to cancer
1. Chromosome rearrangements
• Change in structure of one or more native chromosome
• Changes caused by deletions, duplications, inversions and translocation
2. Gene duplication
• Have additional copies of gene lead to too much of particular protein
3. Point mutation
• Affecting the activity of protein, or prevent its normal regulation
4. Amplifications
• mRNA stability increased leading to overexpression of normal protein
What are the 3 main types of onco-gene activation
increased protein concentration, increased enzyme or protein activity, regulation loss
Describe how RAS act as proto-oncogene
- They switch between an active state (GTP-bound) and an inactive state (GDP-bound.)
- GTP is normally hydrolysed by GTPase activity and GTPase-Activity Accelerating protein (GAPs).
- GDP is then exchanged for GTP using Guanine Nucleotide Exchange Factors (GEFs) to activate Ras
• In mutated cells, Ras is permanently active as the GTPase part is dysfunctional meaning cell division occurs uncontrollably
What are the most common RAS mutations and what is their difference
The three most clinically
significant RAS proto-oncogenes are:
1. HRAS
2. NRAS
3. KRAS
20-30% of all tumours display mutations in these genes which code for 4 homologous Ras
proteins: HRAS, NRAS, KRAS4A and KRAS4B. These all have the same set of downstream
effectors, but differences in their post-translational modifications cause differences in their
signalling pathways.
