L11 - Mutations And Cancer Flashcards
Mutations
- Responsible for diversity of genes found among organisms
- can have major, minor, positive or no effects on resulting protein structure and function
Mutation locations
In body: - germ line: passed on - local/somatic: not whole body In DNA: - protein-coding region - introns - 5’/3’ UTR
Types of mutations
- large scale alterations: chromosomal rearrangements
- small scale alterations: one or few nucleotides
Types of small scale alterations
Substitution, indels
Types of substitution mutation
Silent, mis-sense, nonsense
Indels - 1 or 2 nts
Causes frameshift
Could lead to truncated protein
Truncated protein
Shortened protein due to premature STOP codon
Indels - 3 nt-pair
Maintained frameshift
Wild-type beta-globin
5’ GAG 3’
- Glu - (acidic, -ve charge)
Normal hemoglobin
RBC: maximise surface area, flexible - can squeeze through tiny capillaries
Sickle-cell beta-globin
5’ GUG 3’
- Val - (hydrophobic)
Sickle-cell hemoglobin
RBC is more rigid - can get clogged more easily in capillaries
Sickle cell anaemia
- Missense substitution mutation
- result of accumulative effect: needs to happen to enough hemoglobins in RBC
Importance of checkpoints
Appropriate molecular regulation of cell division critical for normal growth, development and maintenance
Maturation promoting factor (MPF) function
phosphorylates many other proteins and allows mitosis to commence
Maturation promoting factor (MPF) composition
Specific complex of cyclin and cyclin dependent kinase (CDK)
Cyclin
- Protein fluctuating throughout cell cycle
- Many different forms - e.g cyclin D, E, A, B
Cyclin dependent kinase (CDK)
- Kinase that is phosphorylated/activated when attached to cyclin
- Many types
Stop and go signals
Gene products associated with checkpoints
Go signals
Genes that normally stimulate cell proliferation
Stop signals
Genes that normally keep proliferation in check (inhibition)
If stop/go don’t work correctly due to mutation
Uncontrolled cell growth (cell escaped cell cycle control) and can result in tumours
Cancer
Mutation in regulatory genes in somatic cells = uncontrolled cell division for that cell = can eventually lead to cancer
Types of cancer-causing mutations
Genetic predisposition, acquired
Genetic predisposition
In ALL CELLS of body
- inherited or de-novo
- issue/deficiency in a gene (typically one copy)
- doesn’t guarantee cancer but higher risk due to being further along path
Acquired
Locally and initially in ONE CELL
- due to environmental mutagens (E.g UV damage, smoking, carcinogens, viruses, drugs, treatments)
Go signal specific to cancer
Proto-oncogenes
- mutation causes proto-oncogenes to become oncogenes
= over-activation (render them constitutively active) = uncontrolled + accelerated cell growth
Proto-oncogene examples
Ras (GTPase in G protein), Myc (transcription factor)
Stop signals specific to cancer
Tumour suppressor genes
- mutation causes deactivation (no longer function)
= no inhibition of division of cells with damaged DNA
= uncontrolled cell growth
Examples of tumour suppressor genes
P53/TP53 (most common cancer-causing mutation, transcription factor), BRCA1/BRCA2 (associated with breast cancer + other cancer types)
Pathway to cancer
Typically, multiple mutations (1-10) within the same cell are required for it to become fully cancerous
Biopsy
Sample tumour itself to see possible cancer-causing mutations within
- blood samples are not as useful for tumours/solid tumours
Ras (proto-oncogene) normal function
1) ligand binds to receptor
2) Ras activated with ATP
3) protein kinases activated
4) transcription factor responds (activator)
5) protein that stimulates cell cycle produced (GO)
Mutated Ras (oncogene) function
1) no ligand bound but Ras activated
2) DNA transcribed via signal transduction when it shouldn’t
3) overexpression of GO protein
P35 (tumour suppressor gene) normal function
1) DNA damaged (by UV light)
2) protein kinases activated
3) P35 transcription factor activated
4) protein that inhibits cell cycle made
5) damaged DNA not replicated
Mutated P35 function
1) DNA damaged (by UV light)
2) protein kinases activated
3) P35 transcription factor NOT activated
4) inhibitory protein absent
5) damaged DNA replicated
