Oncogenes and Tumour Suppressors Flashcards
What are the hallmarks of cancer
Sustaining proliferative signalling Evading growth suppressors and apoptosis Resisting Cell Death Inducing angiogenesis Enabling replicative immortality Activating invasion and metastasis
Where are the checkpoints in the cell cycle and what is their purpose
At the end of G1, S, and the end of G2
Ensures genetic fidelity
What is the role of cyclins in cell cycle checkpoints
Proteins accumulate or are destroyed during the cycle, including cyclins, cyclin-dependent kinases, and cyclin-dependent kinase inhibitors.
Activation of a cyclin can drive a cell through a checkpoint.
What are proto-oncogenes
Proto-oncogenes code for essential proteins involved in maintenance of cell growth, division and differentiation
What does a mutation in proto-oncogenes result in
Conversion to oncogenes, whose protein product does not respond to control influences
Give examples of oncogenes
MYC
RAS
ERB
SIS
What are the ways in which proto-oncogenes can be converted to oncogenes
Deletion Point mutation Gene amplification Insertional mutagenesis (from viral infection) Chromosomal translocation
What does a deletion or point mutation in the coding sequence for a proto-oncogene lead to
aberrantly active protein
What does gene amplification in the coding sequence for a proto-oncogene lead to
overproduction of the protein
What does insertional mutagenesis or chromosomal translocation in the coding sequence for a proto-oncogene lead to
Formation of:
Chimaeric genes, which may just lead to a rise in protein level (e.g. Burkitt’s lymphoma)
or
A new fusion protein (e.g. by the Philadelphia chromosome)
Describe the Philadelphia chromosome and how an mutation may lead to cancer
Chromosome 9 and 12
2 Key areas: ABL and BCR region
Occasionally, there is chromosomal translocation, and ABL swaps over to chromosome 22.
The result of the combination of BCR and ABL leads to cancer
What is the effect of proto-oncogenes on signal transduction pathways
Activation of proto-oncogenes to oncogenes disrupts normal activity. These oncogenes may interfere with any of the signal transduction pathways
Describe the RAS pathway and why a mutation may lead to tumour formation
Ras is a protein produced by a proto-oncogene.
It’s a membrane-bound GTP-ase linked to cell proliferation.
When Ras dephosphorylates GTP to GDP (during activation of RAF), it is switched off
Mutant Ras is unable to dephosphorylate and therefore remains active when it shouldn’t be
Give some examples of proto-oncogenes
SRC MYC JUN Ha-RAS Ki-RAS
What are tumour suppressor genes
Tend to be inhibitory, where the coded proteins whose function is to regulate cellular proliferation, maintain cell integrity E.g. RB
How many copies of the tumour suppressor gene are there in a cell and how does it affect the result of a mutation
Each cell has two copies of each tumour suppressor gene.
Mutation or deletion of one gene copy is usually insufficient to promote cancer.
Mutation or loss of both copies means loss of control.
What do cancers due to tumour suppressor gene damage often present with
Family history of related cancers
Tumours earlier in life than usual
Tumours in multiple organ systems
Bilateral tumours occurring in paired organs
Give an example of Knudsons two hit hypothesis
retinoblastoma
hereditary/sporadic - involves one eye
Hereditary - unilateral or bilateral and multifocal
What is retinoblastoma and what is it due to
Malignant cancer of developing retinal cells, which is due to either sporadic or hereditary disease
Due to the mutation of the RB1 tumour suppressor gene on chromosome 13914
RB1 encodes a nuclear protein that is involved in the regulation of the cell cycle
What does retinoblastoma present as and what is the treatment
Presents as a chalky eye, and treatment requires removal of the eye.
Why are proto-oncogenes rarely hereditary but tumour suppressor genes sometimes hereditary
Proto-oncogene mutation is rarely hereditary, as you’d be born as a ball of cancer.
TS gene mutations can be passed on because of the need for both copies to be damaged before disease develops.
What must TS genes be able to do in order to suppress the neoplastic phenotype (functional classification)
Regulate cell proliferation, growth, and the cell cycle
Maintain cellular integrity
Regulate cell death (apoptosis)
Act as nuclear transcription factors, DNA repair proteins, or cell adhesion molecules
Describe the p53 gene
Known as the guardian of the genome
Works in conjunction with MDM2
Involved in regulating p53 target genes and protein-protein interactions
Mutated in most cancers
Explain why mutants of p53 are shown in phenotype easily
Mutants of p53 act in a dominant manner and mutation of a single copy is sufficient to get dysregulation of activity (this is because it forms a dimer)
What is a common mutation in the APC gene and what doe sit result in
Due to a deletion in 5q21 resulting in loss of APC gene (tumour suppressor gene).
Involved in cell adhesion and signalling
Sufferers develop multiple benign adenomatous polyps of the colon and there is a 90% risk of developing colorectal carcinoma.
By which pathway do APC proteins act in and what does it do
WNT signalling pathway to alter transcription and growth
APC protein is a negative regulator of b-catenin, thereby preventing uncontrolled cell division.
Compare oncogenes to TS genes
Genes active in tumour vs inactive
Specific translocations/point mutations vs deletions
Mutations rarely hereditary vs inherited possible
Dominant at all cell levels vs recessive
Broad tissue specificity vs considerable
Leukaemia and lymphoma vs solid
Give some examples of TS genes
p53 BRCA1 PTEN APC P16-INK4A MLH1
