Oncogenes and Tumour Suppressor Genes Flashcards
What are the 6 hallmarks of cancer
- Disregard of signals to stop proliferating
- Disregard of signals to differentiate
- Capacity for sustained proliferation
- Evasion of apoptosis
- Ability to invade
- Ability to promote angiogenesis
What does a cell cycle checkpoint do and why
Arrest growth to ensure genetic fidelity by allowing the cell to check that everything is okay
What can permanent activation of a cyclin do
Drive a cell through a cell cycle checkpoint
What is the role of a proto-oncogene (7)
Code for essential proteins involved in the maintenance of cell growth, division and differentiation such as:
- Growth factors
- Growth factor receptors
- Intracellular transducers (signaling proteins)
- Intracellular receptors
- Transcription factors
- Cell cycle regulatory proteins
- Cell death regulators
What is the difference between a proto-oncogene and an oncogene
A single mutation which means the protein product no longer responds to control influences, can be single base mutation
Give 4 examples of proto-oncogenes that can be converted to oncogenes
SRC, MYC, Ki-RAS, Ha-RAS
What 4 mechanisms can convert a proto-oncogene to oncogenes
Mutation in the coding sequence, gene amplification, chromosomal translocation, insertional mutagenesis
What is gene amplification and what does it cause
Overproduction of normal protein because of multiple gene copies
What does a mutation in the coding sequence cause, what are examples of mutations in the coding sequence
Point mutations or deletions, causes an aberrantly active protein
What is a chromosomal translocation and what does it do? Give an example of a disease it causes
Chimaeric genes, its a strong enhancer that increases normal protein levels
What is an insertional mutagenesis? How can you get one? Example
A fusion to actively transcribed genes that overproduces proteins or a fusion protein that is hyperactive, can get one through viral infection, e.g. Philadelphia chromosome
How many copies of a proto-oncogene need to be damaged to give oncogenic properties
1
SRC: function, mechanism of activation, location, associated cancers?
Tyrosine kinase, over expression/C terminal deletion, cytoplasmic, breast/colon/lung
MYC: function, mechanism of activation, location, associated cancers?
Transcription factor, translocation, nuclear, Burkitt’s lymphoma
JUN: function, mechanism of activation, location, associated cancers?
Transcription factor, over expression/deletion, nuclear, lung
Ha-RAS: function, mechanism of activation, location, associated cancers?
G-protein, point mutation, cytoplasmic, bladder
Ki-RAS: function, mechanism of activation, location, associated cancers?
G-protein, point mutation, cytoplasmic, colon/lung
How does RAS become activated and deactivated
Binds GTP to make RAS active, then dephosphorylation to GDP makes it inactive
What cell activity are RAS proteins central to
MAPK cascade (mitogen activated protein kinase)
Which tumour are RAS oncogenes common in and rare in
Rare in breast cancer and found in 95% of pancreatic cancers
Which codon mutations inhibit GTP hydrolysis
12 (Gly), 59 (Ala) and 61 (Gln)
What is different about proto-oncogenes and tumour suppressor genes? What is the exception
Mutations are required in both copies of TSG to promote oncogenic activity rather than the one, p53 gene is the exception
What features are there of inherited cancers (6)
- Family history of related cancers
- Unusually early age of onset
- Bilateral tumours in paired organs
- Synchronous or successive tumours
- Tumours in different organ systems in same individual
- Mutations inherited through the germline
What mutation incurs retinoblastoma (gene, type of gene, chromosome)
RB1 TSG mutation on 13q14
How can you tell the difference between sporadic retinoblastoma and hereditary
Sporadic = usually only one eye Hereditary = can be unilateral, bilateral or multifocal
What does RB1 encode
A nuclear protein that is involved in regulating cell cycle in developing retinal cells
What are the functional classes of TSGs (8)
- Regulate cell proliferation
- Maintain cellular integrity
- Regulate cell growth
- Regulate the cell cycle
- Nuclear transcription factors
- DNA repair proteins
- Cell adhesion molecules
- Cell death regulators
What is Knudsons 2 hit hypothesis regarding inherited and sporadic TSG cancer
Inherited TSG cancers usually mean that people are born with one mutant TSG allele and acquire the other one, sporadic means they acquire both e.g. through smoking
p53: function, location, associated cancers?
Cell cycle regulator, nuclear, many (colon, breast, bladder, lung, etc)
BRCA1: function, location, associated cancers?
Cell cycle regulator, nuclear, breast, ovarian and prostate
PTEN: function, location, associated cancers?
Tyrosine and lipid phosphatase, cytoplasmic, prostate, glioblastoma
APC: function, location, associated cancers?
Cell signalling, cytoplasmic, colon
p16-INK4a: function, location, associated cancers?
Cell cycle regulator, nuclear, colon and others
MLH1: function, location, associated cancers?
Mismatch repair, nuclear, colon, gastric
What is special about p53 (bad thing)
A mutation in a single copy is sufficient to get dysregulation of activity
What does p53 guard (list) (6)
Metabolic homeostasis Antioxidant defence DNA repair Growth Arrest Senescence Apoptosis
What activates/stabilises p53?Examples?
DNA damaging agents, e.g. chemicals or UV
When activated what does p53 activate (3)
p21 (Waf1), MDM2 (hDM2), BAX
What p21(Waf1) do
Binds and inhibits cyclin dependent kinases and cyclins to arrest cell cycle
What MDM2 (hDM2) do
Binds to and inactivates p53 (autoregulatory loop)
What BAX do
Promotes apoptosis
What family does BAX belong to
BCl-2
What is the function of p53 (words)
Tries to repair cells that have undergone damage- if this doesn’t happen, p53 commits the cell to apoptosis
What happens to cells in which both the cell and p53 is damaged
Division goes forward- these cells are the ones that often continue to cancer, but sometimes to die because damage is too great
What is the most commonly mutated gene in human cancer? How many cancers is this present in
p53, over 50%
What domain do 98% of p53 transforming mutations occur
DNA binding domain
What mutation and which chromosome results in APC, what does the mutation do
Deletion in 5q21, results in loss of APC TSG gene
What does APC gene do, what does it control?
Involved in inhibiting transcriptional up regulation in the nucleus, it controls beta catenin
What does beta catenin do
Drives proliferation via the upregulation of transcription
What disease does loss of APC gene result in
FAP - familial adenomatous polyposis
Differences between oncogenes and TSGs (6)
Gene active in tumour vs inactive in tumour
Specific translocations/point mutations vs deletions or mutations
Mutations rarely hereditary vs mutations can be inherited
Dominant at cell level vs recessive at cell level
Broad tissue specificity vs considerable tumour specificity
Leukaemia and lymphoma vs solid tumours
Describe the development of colorectal cancer, from normal epithelium to metastasis and the three mutations/stages in between
normal epithelium -> APC mutation -> hyper proliferative epithelium -> Ki-Ras mutation -> adenoma -> p53 -> carcinoma -> metastasis
