Mechanisms of disease - cell growth and cell differentiation Flashcards
What is the basic mechanisms responsible for turning a zygote into a mature organism?
- cell growth
- differentiation
Cell growth followed by differentiation - more cells and then becoming more complex
(they sometimes overlap)
What are diseases releated to cell growth and differentation?
- Developmental conditions - related to cell growth and/or differentiation
- Neoplasia - cancers and tumours
- Others - eg. Cardiac hypertrophy
How is cell growth carried out?
- Hypertrophy - bigger cells
- More proteins, more membranes etc.
- Elevated protein synthesis is a big drive of increased cell size
- Eg. The heart
- Hyperplasia - more cells
- Caused by cell division or proliferation - cell cycle
- Balanced by cell death
What are differentiated cells called?
Post-miotic
As a result of gene expression, cell morphology and function changes
What are the different signals that govern cell growth and differentiation?
Intracellular signals
Extracellular signals
- Ligand –> receptor –> intracellular cascade
- Paracrine - produced locally that has the appropriate receptor
- Autocrine - binds to its our receptor on ligand
- Endocrine - hormones for distant effect
- Proteins that stimulate proliferation and promote survival - mitogens eg. Growth factors
- Proteins that induce differentiation and inhibit proliferation
- Proteins that induce apoptosis
Where do signals of cell growth and differentiation work?
Promotors of key gene
Promoters act as ‘co-incidence detectors’ - determine how much gene is expressed
What are quiescent cells?
= cell that leave the cell cycle in G0
- They can either re-join the cell cycle
- Or begin journey into differentiation
However the fate of any cell is apoptosis
What is the FACS analysis?
Analysis of cell DNA content
- If a DNA stain is applied, FACs can measure the DNA content of every cell in a population
- Used to plot a graph - amount of DNA vs number of cells
What is the shape of a FACS analysis graph where cells are more proliferative?
What do the different cell cycle checkpoints do?
G1/S Restriction point - checks DNA damage, cell size, metabolite/nutrient stores
G2/M checkpoint - checks DNA completely replicated and that DNA isn’t damaged
Mitosis - checks on chromosomes positioning aligned on spindle
Main site of control for cell growth = G1
How is cyclin-CDK activty regulated?
- High turnover by cycles of synthesis (gene expression) and destruction (by proteasome)
- Post translational modification by phosphorylation - may result in activation, inhibition or destruction
- Dephosphorylation
- Binding of cyclin-dependent kinase inhibitors (CDKIs)
How does a retinoblastoma protein negatively regulate the cell cycle?
Retinoblastoma protein = key substrate of G1 and G1/S cyclin-dependant kinases
What are the sequential activities in the cell cycle?
What is there is DNA damage in the cell cycle?
- Stop the cycle - cyclin dependent kinase inhibitors
- Attempt DNA repair - eg. Mismatch repair
- If repair impossible - programmed cell death
What is TP53?
= tumour protein 53
- TP53 gets destructed by proteasomes - so hardly any in the cell
What happens to TP53 if there is DNA damage?
–> Leads to kinase activation –> phosphorylate TP53
Phosphorylate TP53 can no longer be destructed by proteasomes - it will accumulate and exert biological affects on the cell:
- Drive expression of CKI –> cause cell cycle arrest
- Activation of DNA repair
- Repair not possible –> apoptosis
What is the purpose of TP53 in cancer?
TP53 loss-of-function mutations are amongst the most frequent in cancer
- Prevent apoptosis –> do not die
- Prevent DNA repair –> more mutations –> cancer progression
- Prevent cell cycle arrest –> cells grow faster
What does chemotherapy do?
Traditional drugs act on cell cycle and stop proliferation and induce apoptosis
S-phase drugs - cause DNA damage and block repair mechanisms
M-phase drugs - target mitotic spindle
- Vinca alkaloids - stabilise free tubulin and prevent microtubule - can’t make spindle
- Paclitaxel - stabilises microtubules –> arrests cell in mitosis
