Oncogenes and tumour suppressors Flashcards
The hallmarks of cancer
- Sustaining proliferative signalling
- Evading growth suppressors
- Activating invasion and metastasis
- Enabling replicative immortality
- Inducing angiogenesis
- Resisting cell death
Added hallmarks of cancer
EMERGING HALLMARKS -Deregulating cellular energetics -Avoiding immune destruction ENABLING CHARACTERISTICS -Genome instability and mutation -Tumour-promoting inflammation
The cell cycle
- Cycle checkpoints (growth arrest ensure genetic fidelity)
- Specific proteins accumulate/are destroyed during the cycle (cyclins, cycle dependent kinases, cycle dependent kinase inhibitors)
- Permanent activation of a cyclin can drive a cell through a checkpoint
Proto-oncogenes
- code for essential proteins involved in maintenance of cell growth, division and differentiation
- mutation converts a proto-oncogene to an oncogene, whose protein product no longer responds to control influences (can be single mutation)
- oncogenes can be abnormally expressed, over-expressed or abnormally active (eg: MYC, RAS, ERB, SIS)
Oncogene activation
- Begin with normal proto-oncogene
- Mutation in the coding sequence (point mutation of deletion)
- Gene amplification (multiple gene copies)
- Chromosomal translocation (chimaeric genes)
- Insertional mutagenesis (eg: viral infection)
Philadelphia chromosome
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Proteins involved in signal transduction are potential critical gene targets
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Activation of proto-oncogenes to oncogenes disrupts normal activity
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Mutant Ras has abnormal activity
- Upon binding GTP, Ras becomes active
- Dephosphorylation of GTP to GDP switches Ras off=mutant Ras faills to dephosphorylate GTP and remains active
Ras signalling
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Oncogenes and human tumours: SRC
Function: tyrosine kinase
Mechanism of activation: overexpression/C-terminal deletion
Location: cytoplasmic
Associated human cancers: breast, colon, lung
Oncogenes and human tumours: MYC
Function: transcription factor
Mechanism of activation: translocation
Location: nuclear
Associated human cancers: Burkitt’s lymphoma
Oncogenes and human tumours: JUN
Function: transcription factor
Mechanism of activation: overexpression/deletion
Location: nuclear
Associated human cancers: lung
Oncogenes and human tumours: Ha-RAS
Function: G protein
Mechanism of activation: point mutation
Location: cytoplasmic
Associated human cancers: bladder
Oncogenes and human tumours: Ki-RAS
Function: G protein
Mechanism of activation: point mutation
Location: cytoplasmic
Associated human cancers: colon, lung
Tumour suppressor genes
- typically proteins whose function is to regulate cellular proliferation and maintain cell integrity (eg: RB)
- each cell has 2 copies of each tumour suppressor gene
- mutation or deletion of 1 gene copy is usually insufficient to promote cancer=mutation or loss of both copies means loss of control
Knudson’s two hit hypothesis
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Inherited cancer susceptibility features
- 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
Retinoblastoma
- malignant cancer of developing retinal cells
- sporadic disease usually involving one eye
- hereditary cases can be unilateral or bilateral and multifocal
- due to mutation of RB1 tumour suppressor gene on chromosome 13q14
- RB1 encodes nuclear protein involved in cell cycle regulation
Functional classes of tumour suppressor genes
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Tumour suppressor genes and human tumours: p53
Function: cell cycle regulator
Location: nuclear
Associated human cancers: many (colon, breast, bladder, lung etc)
Tumour suppressor genes and human tumours: BRCA1
Function: cell cycle regulator
Location: nuclear
Associated human cancers: breast, ovarian, prostate
Tumour suppressor genes and human tumours: PTEN
Function: tyrosine and lipid phosphatase
Location: cytoplasmic
Associated human cancers: prostate, glioblastoma
Tumour suppressor genes and human tumours: APC
Function: cell signalling
Location: cytoplasmic
Associated human cancers: colon
Tumour suppressor genes and human tumours: p16^-INK4A
Function: cell cycle regulator
Location: nuclear
Associated human cancers: colon and others
Tumour suppressor genes and human tumours: MLH1
Function: mismatch repair
Location: nuclear
Associated human cancers: colon, gastric
p53
- ‘the guardian of the genome’
- tumour suppressor gene
- mutants of p53 act in a dominant manner and mutation of a single copy is sufficient to give activity dysregulation
APC tumour suppressor gene
- familial adenomatous polyposis coli
- due to deletion in 5q21 resulting in loss of APC gene (a tumour suppressor gene)
- APC gene involved in cell adhesion and signalling
- sufferers develop multiple benign adenomatous polyps of the colon
- 90% risk of developing colorectal carcinoma=APC gene mutation is a frequent event in colon cancer
- APC gene participates in WNT signalling pathway
- APC protein is a negative regulator of beta-catenin (preventing uncontrolled cell division)
The route to cancer
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The development of colorectal cancer
- Normal epithelium
- Hyperproliferative epithelium
- Adenoma
- Carcinoma
- Metastasis
Oncogenes
- 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
COSMIC
-Catalogue Of Somatic Mutations In Cancer
