Cancer 2:Oncogenes and tumour supressor genes Flashcards
What is the cancer cell phenotype (hallmarks of cancer)
- Disregards signal to stop proliferating
- Disregards signals to differntiate
- Capacity for sustained proliferation
- Evasion of apoptosis
- Ability to invade
- Ability to promote angiogenesis
State the cell cycle and the amount of time in each
G1- 10hrs
S- 7.5hrs
G2- 3.5hrs
M=1hrs
How long does the cell cycle occur for
22hrs
What is the purpose of cycle checkpoints
growth arrest ensures genetic fidelity
What are the cycel checkpoint
After G1:
check for cell size/favourable environmental factors
check for DNA damage
After S: none
After G2: check for damaged/unduplicated DNA, check for unduplicated centrosomes
After metaphase of M: check for chromosome attachment to the mitotic spindle
Which proteins are accumulated and destroyed during the cell cycle
Cyclins, cycle dependent kinases, cycle dependent kinase inhibitors
What drives a cell through a checkpoint
Permanent activation of a cyclin can drive a cell through a checkpoint.
What are proto-oncogenes
code for essential proteins involved in maintenance of cell growth, division and differentiation.
What is the difference between proto-oncogene and oncogene
following a mutation (1 can be enough!), the protein product no longer responds to control influences
What can be abnormal about an oncogene
aberrantly expressed, over-expressed or aberrantly active.
Outline the methods of oncogene actiation
- Mutation in coding sequence (point mutation)
- Gene amplificatin (multiple gene copies i.e. too much proto-oncogene)
- Chromosomal translication (chimaeric genes)
- Insertional mutagenesis (viral infection)
By what mechanism does oncogene activation then cause abnormal protein activity
- Mutation in coding sequence (point mutation) –> ABERRANTLY ACTIVE PROTEIN
- Gene amplificatin (multiple gene copies) –> OVERPRODUCTION OF NORMAL PROTEIN
- Chromosomal translication (chimaeric genes)
- Insertional mutagenesis (viral infection)
3/4 CAN LEAD TO: STRONG ENHANCER (increases normal protein level e.g. burkitt's lymphoma) ... strong enhancer from another chromosome during fusion which increaes expression of the protein
or
FUSION TO ACTIVELY TRNASCRIBED GENE OVERPRODUCES PROTEIN OR FUSION PROTEIN IS HYPERACTIVE (e.g Philadelphia chromosome)
What is the philalphia chromsome
Chr 9 ABL switches with the short arm on 22
left behind: 9q+, Ph22q- (with BCR-ABL)
BCR-ABL is powerfullt expressed…. few situations where a SINGLE DNA CHANGING event can cause cancer
How are signal transduction proteins relvant in cancer
Proteins involved in signal transduction are potential critical gene targets (proto-oncogenes)
Give types of receptors which could be protooncogenes
Nuclear/cytosolic receptor
Tyrosin kinase receptor
G-protein coupled receptor
How does each signal transduction protein affect proliferation
Nuclear/cytosolic receptor: (imapcts transcription/translation–> proliferation)
Tyrosine kinase (phosphorlation cascade–> proliferation)
GPCR: (activates kinase casade–> phosphoryation cascade–> proliferation)
Give examples of proteins in each of the proto-oncogenes
Tyrosine: membrane: met (heptaocyte growth factor receptor), neu (HER2), inside membrane src, ret
GPCR: membrane: ras, gip-2, inside membrane: raf, pim 1 (confused as I thought ras and raf was tyrosine kinase)
Intraacellular: myc, fos, jun
What does RAS do
Ras (on the membrane)
Binds GTP, activating it. This then activates RAF. (inside of membrane) to cause signalling cascade which increases proliferation
Dephosphorylation of the GTP to GDP switches RAS off.
RAF will stop
How can RAS go wrong
Mutant RAS fails to dephosphorylate GTP and remains active.
This then keeps on stimulating RAF and thus proliferation
How does RAS and RAF work
Ligand binds receptor (e.g. tyrosine kinase)
RAS is tethered to the membrane.
RAS binding GTP will then allow it to bind RAF, activating it.
Dephopsorylation will cause the RAF to dissocaite
Why can damage to a single proto-oncogene, not both of the genes, cause cancer
Because it is now damaged.
Having a normal proto-oncogene will not then remove the activty of the oncogene
Outlne the function of SRC proto-oncogene gene. How can it be activated .
Give examples of human cancers associated with this gene
Where the product of the gene located
Tyrosine kinase
Mechanism of activation: overexpression/C-terminal delection
Breast, colon, lung
Protein in the cytoplasm
Outlne the function of Myc proto-oncogene gene. How can it be activated .
Give examples of human cancers associated with this gene
Transcription factor (for lots and lots of genes including c-Myc which does cyclin D1 and others)
Mechanism of activation: translocation
Location of protein (TF) is nuclear
Human cancers: Burkitt’s lymphoma
Outlne the function of Jun proto-oncogene gene. How can it be activated .
Give examples of human cancers associated with this gene
Transcription factor
Mechani of activation:
Overexpression/ deletion
Location of protein is nuclear
Human cancers: Lung
What are the two types of RAS and what are they associated with
Ha-RAS and Ki-RAS…. they are G proteins
Outline the function of Ha-RAS and Ki-RAS, how are they activated, where are they present and the assoaited human cacners
BOTH: function is G protein, point mutation is mechanism of activation and location is cytoplasmic
Ha-RAS: bladder
Ki-RAS: colon/lung
What is a tumour supressor gene
Typically proteins whose function is to regulate cellular proliferation, maintain cell integrity.
Give an example of a tumour supressor gene
Retinoblastoma protein
t/f each cell has the same number of copies of proto-oncogenes and tumour supressor genes
T… they both have 2 copies
DIFFERENTIATE tumour supressor and oncogene in terms of mutation or deletion
Tumour supressor:
Mutation or deletion of one gene copy is usually insufficient to promote cancer.
Mutation or lost of both copies means loss of control.
need to lose 2 to lose the positive function
Oncogene, only one gene needs mutating to gain a negative acton
Outline the features of inherited cancer susceptibility
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.
Mutation inherited through the germline.
How were tumour supressor genes
Due to inherited cancer susceptibility
What is retinoblastoma
Malignant cancer of developing retinal cells.
Outline the two types of retinoblastoma
SPORADIC… usually affects one eye, in older individuals. Due to mutations built up over the lifetime
HEREDITARY…. Hereditary cases can be unilateral or bilateral and multifocal.
Explain the cause of hereditary retinoblastoma protein
Due to mutation of the RB1 tumour suppressor gene on chromosome 13q14.
RB1 encodes a nuclear protein that is involved in the regulation of the cell cycle.
Outline the functional classes of tumour supressor genes
OVERALL: SUPPRESS THE NEOPLASTIC PHENOTYPE
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
Outlne the function of p53 tumour suppressor gene. How can it be activated .
Give examples of human cancers associated with this gene
Cell cycle regulator
Nuclear
Many (colon, breast, bladder, lung etc)
Outlne the function of BRCA1 tumour suppressor gene. How can it be activated .
Give examples of human cancers associated with this gene
Cell cycle regulator
Nuclear
Breast, ovarian, prostate
Outlne the function of PTEN tumour suppressor gene. How can it be activated .
Give examples of human cancers associated with this gene
Tyrosine and lipid phosphatase
Cytoplasmic
Prostate glioblastoma
Outlne the function of APC tumour suppressor gene. How can it be activated .
Give examples of human cancers associated with this gene
Cell signalling
Cytoplasmic
Colon
Outlne the function of p16-INK4A tumour suppressor gene. How can it be activated .
Give examples of human cancers associated with this gene
Cell cycle regulator
Nuclear
Colon and others
Outlne the function of MLH1 tumour suppressor gene. How can it be activated .
Give examples of human cancers associated with this gene
Mismatch repair
Nuclear
Colon /gastric
What is p53 and why is it different to other tumour suppressor
Although p53 is a tumour supressor gene, mutants of p53 act in a dominant manner and mutation of a single copy is sufficient to get dysregulation of activity.
(i.e. this is different…. as if it is an oncogene! Because oncogene usually only takes 1 mutation whereas TSG usually needs to damage 2 copies).
Because the damage becomes DOMINANT
What is p53 usually bound to and what is the effect
MDM2… usually bound to p53, and this makes p53 inactive
When instruction to release p53 from MDM2, p53 becomes active
What signals p53 to become released from MDM2
Oxidative stress NO Hypotxia Ribonucleotide depletion Mitotic apparatus dysfunction Oncogene activation DNA replication stress Double-strand breaks telomere erosion
What happens when p53 is released
It works with other p53 proteins to activate either regulation of p53 target genes (in mild and physioligical stress) or of protein-protein interactions in sever stress
What can activated p53 do
Mild stress:
Metabolic homeostasis/antioxidant defence/DNA repari/growth arrest
Sever stress:
senescene
apoptosis
What is APC tumour supressor gene associated with
Familial adenomatous polyposis coli
In FAP what is the genetic change
deletion in 5q21 resulting in loss of APC gene (tumour suppressor gene)
What is APC involved in
Involved in cell adhesion and signaling in the WNT pathway
apc control the activity of b-catenin and thereby preventing uncontrolled growth
Mutation of APC is frequent event in colon cancer
Outline the route to cancer in colon cancer
Damage to APC–>hyperproliferative state (not cancer yet)–> DNA metholation (K-RAS) –> adenoma –> p53 damage –> carcinoma –>metastasis to liver
Compare oncogene and tumour supressor gene
…..
What is meant by critical gene target
in 90% of the genome, mutations don’t matter.
In critical gene targets…. TSG/proto-oncogenes, can be problematic
