Oncogenes and tumour suppressor genes Flashcards
1
Q
What are the major functional changes in cancer?
A
- Increased growth
- Failure to undergo apoptosis or senescence
- Loss of differentiation
- Failure to repair DNA damage
2
Q
What are proto-oncogenes?
A
- have tightly regulated physiological function, usually in growth stimulation
- Mutations will cause them to become oncogenes
3
Q
Non-defective vs Acutely transforming vs acutely transforming non-defective oncogenic retroviruses
A
- Non-defective just have the classical genes (Gag - codes for capsid; Pol - polymerase; and env - envelope protein). They cause tumours by insertional mutagenesis
- Acutely transforming - cause tumours by transduction of the viral oncongene. Defective because they are missing part of the viral genome (env is replaced by viral oncogene). Switches normal gene to a tumour gene - cant make normal environment, so have to coexist in host cell.
Acutely transforming non-defective - has all the non-defective genes, but also an src gene (rous sarcoma virus)
4
Q
What is the retroviral life cycle?
A
- Reverse transcription can make a copy of the RNA to DNA and then make a second strand
- It then inserts this into host DNA
- At the end of the viral genome is a long terminal repeat, which forces the transcription
- genes can then be translated - make viral proteins which then bud off
5
Q
How are genes activated by promoter insertion?
A
- Insertion point of tumours are around the beginning of the myc proto-oncogene
- results in an insertional mutation - long terminal repeat forces production of myc protein
- aberrant expression, no longer controlled by host’s transcriptional control
6
Q
What are the chromosomal translocations in Burkitt’s lymphoma?
A
- translocation between chr8 (myc) and chr14 (ig heavy chain)
OR - chr8 and chr2 or 22 (ig light chains)
- In all cases -> unregulated expression of myc
7
Q
What are the chromosomal translocations in CML?
A
- 9 and 22 - makes a gene resulting in novel fusion protein
- Break-point cluster region (BCR) fusion with ABL - enhances TK activity so always switched on
8
Q
What is the functional activity of proto-oncogenes?
A
- Most cases, products of oncogenes are components of growth stimulatory pathways
- Signals from GFs bind their receptors and activate the mitogen-activated protein kinase (MAPK) pathway, to switch gene transcription in the nucleus
- In tumours cells, overexpression or mutation activates such proto-oncogenes, whereas in normal cells, their expression is tightly regulated
9
Q
What is the receptor TK pathway?
A
- Binding of GF causes autophosphorylation of receptors
- Allows complex to bind to the phosphate
- The Sos region of the complex is a guanine exchange factor - causes exchange of GDP -> GTP, switching on the ras and triggering the pathway
- Over time Ras hydrolyses GTP back to GDP - automatically switching it off
- Mutation means itll be permanently on
10
Q
What have we found from tumour cell cultue assays?
A
- assays for presence of oncogenes in DNA from human tumours
- transfect DNA, culture for 2 weeks and allow transformed cells to grow.
- See that normal cells can be converted to tumour cells
- Most cases have detected ras oncogenes
11
Q
What happens in oncogenic mutations in k-Ras?
A
- Mutations at gly12 abolishes GTPase activiy, preventing kras switching off
12
Q
What are Tumour suppressor genes?
A
- Usually regulate cell cycle checkpoints (eg rb), differentiation (APC) or DNA repair (BRCA1)
- Phenotype of mutations causing cancer is usually recessive at cellular level (still have normal gene copy that can provide some functionality), but act as dominant at organism level (high probability that in one cell, the functional copy will be inactive)
- Inheritence of a non-functional TSG is most common cause of heritable cancer
13
Q
TSGs and cell cycle regulation
A
- TP53 causes expression of a CDKI - blocking CDK and arresting the cycle if there is damage
- RB1 protein - binds to E2F, stopping the cell from entering S-phase. Usually pRB is phosphorylated by CD4-CyclinD to allow E2F action
14
Q
What do the oncogenes do in DNA tumour viruses?
A
- Have late (make capsid) and early genes (force host to start DNA synthesis) genes
- E6 protein binds Tp53 and targets it for degradation
- E7 blocks the binding to TF and prevents RB1 from capturing E2F
- E5 increases EGF efficiency
- E2 causes the switch between E and L genes
- When it inserts into the host DNA, it has to become linear - if the break is in E2 region, then there will be no switch, and so early genes will continually keep cycle going
15
Q
How does APC promote b-catenin degradation?
A
- APC binds beta-catenin in a complex, causing its degradation - stops stimulation of growth
- B-catenin can become mutated in a way that APC cannot bind - becomes an oncogene
- Wnt GF binds to receptor, which inhibits the formation of the degradation complex - stimulates growth
