Cell cycle and cancer Flashcards
1
Q
What is the cell cycle?
A
- somatic cells need to replicate and divide
- growth and repair
- method to ensure genetic integrity
- involved in cellular differentiation
- multi-step process with defined checkpoints
- distinct control mechanisms
- regulated by protein complexes that work in specific order
2
Q
What are the 4 stages of the cell cycle? (interphase)
A
- G1 = before DNA synthesis, organelles replicated
- S = duplication occurs
- G2 = proofing of new DNA strand, preparation for cell split
- M = splitting of cell into two
3
Q
Describe the G1 phase
A
- regulated by the G1 CDK cyclins - which serve to initiate the E2F transcription factors
- E2F target genes encode proteins required for DNA replication - DNA pol, nucleotides, CDKs
- E2F default setting is ‘off’ caused by pRB
- negating the effect of pRb is the key
- CDK: cyclins perform this task
4
Q
What are the G1 phase CDK cyclins?
A
- hypo-phosphorylated Rb is complexed to E2F, which prevents activity = no cycling
- mitogenic stimulation; eg growth factors, cytokines, stimulants, FBS = inc cyclinD-CDK4
- cyclin D-CDK4 phosphorylates pRb, causing it to release E2F = cycling
- early response for E2F activity is an induction of cyclinE-CDK2, which maintains G1 transit
5
Q
What are the G1 phase - CDK inhibitors?
A
- cells have an intrinsic ability to counteract the ‘go’ signal elicited by CDKs
- without it, cells would grow forever
- endogenous inhibitors = activated by cytokines, inc. in response to DNA damage, halt cells and decided fate
6
Q
What happens in G2/M phase?
A
- fewer checkpoints in G2/M transit
- once the cells get this far, assumed to be ok
- CyB-CDK1 ensures cells are ready for splitting - correct alignment of chromosomes, spindle fibres have integrity
- faults here tend to be terminal, and dealt with by mitotic machinery
7
Q
What is mitotic catastrophe?
A
- metaphase-to-anaphase
- if chromosomes do not align properly or spindle fibres do not connect
- mitotic catastrophe as cells will not part
- normal process that ensures fidelity of cell quality
- powerful way of disposing cells at end of the cell cycle
8
Q
What is G0 - quiescence?
A
- cell cycle is primarily associated with proliferation
- however a large proportion of cells actually lie dormant and are said to be in G0
- Cells in G0 = contain 1 set of DNA, no active division, resistant to death, can re-enter cell cycle
9
Q
How to track the cell cycle?
A
- cells are stained with a DNA dye
- flow cytometry used to assess the DNA content of individual cells
- peaks indicate the staged of the cell cycle
- DNA profile can inform the state of the cell
- polyploidy
- apoptosis
10
Q
Why does hyper-proliferation occur?
A
- faults normally trigger checkpoints that put a brake of cell cycling
- uncontrolled proliferation in cancer caused by a loss of control of cell cycle
mutations in the cell cycle tend to result in a direct loss of regulatory function - dec p16 = inc cyD-cdk4 = PROLIFERATION
- dec pRb = inc E2F = PROLIFERATION
- dec p53 = dec p21 = inc CDKS = PROLIFERATION
11
Q
What drugs target the cell cycle?
A
- preventing cancer cells from growing = counteract growing signal, neutralise don’t die signal, induce die signal
- drugs that perform these roles = anti-proliferatives, anti-metabolites, cytotoxics
12
Q
Why is it useful to track the cell cycle?
A
- better understanding of what drugs are doing
- how and where drugs work
- guide ways to improve treatment strategies
- generally, effects of drugs are either : cytotoxic, cytostatic
- combination possibilities
13
Q
How can the cell cycle profile be used to recognise cytotoxicity?
A
- etoposide interfered with replication
- disturbs alignment of chromosomes
- can cause certain cancer cells to fie
- profiles can be tracked to assess action and activity
- interpretation :cells empty from G1 and S into G2 = and an inc in sub G1 population
14
Q
What does cytostasis look like on a cell cycle profile?
A
- cancer cell responds to treatment by preventing transit through G2/M
- interpretation = partial restoration of growth control and cells do not grow beyond G2
15
Q
What does cytostasis 2 look like on a cell cycle profile?
A
- cancer is not responding to natural controls and cells proliferate unchecked
- drug reduces cell numbers, but there is no actual killing or a change in DNA profile
- interpretation - drug is cytostatic = causes the cell to regain control of the cell cycle, but does not specifically induce cell death
