Oncogenes and tumour suppressors Flashcards
What are the hallmarks of cancer (cancer cell phenotype)?
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 do proto-oncogenes code for?
Essential proteins involved in maintenance of cell growth, division and differentiation
What can mutation of a protooncogene cause?
It converts the protooncogene into an oncogene whose protein product no longer responds to control influences
What is gene amplification?
Production of multiple gene copies- can occur due to problems with a polymerase protein
What does gene amplification lead to?
Overproduction of gene product
What are chimeric genes?
Genes that are formed by combinations of portions of one or more coding sequences to form new genes
When are chimeric genes a problem?
If one of the pieces of translocated DNA is a promoter leading to upregulation of the other gene portion- occurs in Burkitt’s lymphoma
Or if fusion gene formed produces an abnormal protein e.g. philadelphia chromosomes in CML
What is the Philadelphia chromosome formed by?
Translocation of chromosome segments from chromosomes 9 and 22, they 2 key areas are:
ABL- chromosome 9
BCR- chromosome 22
BCR-ABL fusion gene leads to development of cancer
In terms of signal transduction pathways, what effect can a protooncogene mutating to form an oncogene have?
It can lead to downstream activation of signalling pathways such that they no longer need to respond to upstream stimuli
What normally happens when GTP binds to Ras?
It becomes active and activates the kinase cascade leading to the production of gene regulatory proteins
How is active Ras switched off?
Dephosphorylation of GTP to GDP
What happens in mutant Ras?
It will fail to dephosphorylate GTP meaning that it persists so Ras remains active
What pathway does the Ras pathway belong to?
Complex signalling cascade called mitogen-activated protein kinase cascade (MAPK)
What does Ras code for?
Family of proteins such as Ki-Ras and Ha-Ras which are membrane bound GTPases that are important in stimulation of cell proliferation
What are tumour suppressor genes typically?
Proteins whose function is to regulate cellular proliferation and maintain cell integrity (e.g. retinoblastoma)
How many copies of each tumour suppressor gene does each cell have and what does this mean?
2
Mutation or deletion of just one gene copy is usually insufficient to promote cancer (mutation or loss of both copies means loss of control
What are the features of inherited cancer susceptibility (has led to discovery of tumour suppressor genes)?
Family history of related cancers Unusually early onset Bilateral tumours in paired organs Synchronous or successive tumours Tumours in different organ systems in same individual Mutation inherited through germline
What is retinoblastoma?
Inherited malignant cancer of developing retinal cells
What is retinoblastoma caused by?
Mutation of RB1 tumour suppressor gene on chromosome 13q14
What does RB1 encode?
Nuclear protein that is involved in regulation of cell cycle
What are the functional classes of tumour suppressor genes?
Regulate cell proliferation Maintain cellular integrity Regulate cell growth Regulate cell cycle Nuclear transcription factors DNA repair proteins Cell adhesion molecules Cell death regulators
What is the overall effect of tumour suppressor genes?
Suppress neoplastic phenotype
What examples of tumour suppressor genes are there?
p53 BRCA1 PTEN APC p16-INK4A MLH1
When is p53 inactive?
When bound to MDM2
What is p53 important in?
Lots of stuff including regulation of p53 target genes and protein-protein interactions
How is p53 activated?
Many different types of cellular stress
What is different about p53 from other tumour suppressor genes?
Mutants of p53 act in a dominant way and mutation of a single copy is sufficient to get dysregulation of activity
What does phosphorylation of p53 do?
Destabilises it so it isn’t degraded so quickly and can exert its effects- it is triggered by cellular stress
What is the APC gene involved in?
Cell adhesion and cell signalling
What causes loss of APC gene?
Deletion in 5q21
What do people with APC mutation develop?
Multiple benign adenomatous polyps in the colon
How does APC work?
It participate in WNT signalling pathway to alter transcription and growth
It helps control activity of beta-catenin and prevents uncontrolled growth
In what type of cancer is mutation of APC common?
Colon
How does colorectal cancer develop?
APC in normal epithelium gets mutated and becomes inactive (loss of TSG) leading to hyperprolifertion of epithelium
DNA hypomethylation (epigenetic change) combined with K-ras mutation (oncogene) will make polyps develop into adenomas
Mutation of P53 (guardian of genome) will result in development of carcinoma which can then go onto metastasise
Compare oncogenes and tumour suppressor genes?
Oncogene: Gene active in tumour Specific translocations/point mutations Mutations rarely hereditary Dominant at cell level Broad tissue specificity Leukaemia and lymphoma
Tumour suppressor gene: Gene inactive in tumour Deletions or mutations Mutations can be inherited Recessive at cell level Considerable tumour specificity Solid tumours
