cell cycle, quiescence and senescence in eukaryotes Flashcards
free living cell growth mainly determined by
environ cues eg nutrient supply
In multicellular animals cell growth mainly controlled by
Extracellular signals (from cells around them)
Other processes cells can undergo except for growth/proliferation
stop proliferating Undergo apoptosis (planned cell death) Undergo Necrosis (planned cell death
focus organisms for cell cycle
yeasts, frog eggs and mammalian cells in culture
Hartwell
found first cdc genes and discovered checkpoints
Hunt
discovered cyclin
Nurse
Proved that MPF was cyclnin + CDK
and he isolated human cdk
3 stages of CD cycle
Mitosis, synthesis and growth
checkpoints
Points in the cell cycle where you can ‘put the breaks on’ due to cues/ have to pass ‘tests’
Regulated by cyclin/CDK complexes
Examples of checkpoints
DNA damage, unfavourable extracellular environment (G1)
Incomplete repl (S)
Insufficient cell cycle (G2)
Chromosome incorrectly attache dto mitotic spindle (M)
Cyclin/CDK complexes
allow 2 main checkpoints to be passed (from G2 into mitosis and G1 into S phase)
CDK-cyclin complex formation
cdks constant throughout cell cycle
G2–> M: To make active complex they need to associate with cyclin proteins, which are synthesised during G2 and degraded at end of mitosis (m cyclin), or in the case of the G1–> S checkpoint the cyclin is synthesised during the G1 phase and degraded at the end of S phase (S-cyclin)
When is peak in cdk activity and why (G2–>M)
Mid mitosis
Due to steady accumulation of M cyclin during G2 and then rapid destruction at the end of mitosis
How is the peak in activity achieved? step 1
Why don’t we get a sharp incr
during cylin accumulation, the activity of the complex kept in check by phosphorylation of cdk (as complex is forming) by inhibitory kinase called Wee1- keeps cdk inactive
This is why we don’t get gradual increase in M-cdk (instead sharp)- see prev graph (green part)
step 2
Forming active M-cdk
Once complex accumulated, activating phosphatase called Cdc25 removes phosphates from cdk
Forms active M-cdk complex
step 3
+ve feedback
Active M-cdk/cyclin phosphorylates inactive Cdc25 (has no phosphatase activity), so it becomes active and can carry out phosphorylation
POSITIVE FEEDBACK
Step 4
Drop in cdk activity
Drop in cyclin-cdk activity is rapid
APC activated, adds chains of ubiquitin to cyclins- tagging them for rapid destruction at proteosomes
forms inactive cdk because cyclin degraded
What promotes transition of G1 into S phase
active S-cdk complex
How does a G1/S phase checkpoint prevent repl of damaged dna
Protein machinery recognises different forms of DNA damage- activates p53 protein
In absence of dna damage
p53 kept at low levels in the nucleus, being degraded (and a little synthesised ) by proteosomes
If there is dna damage
Proteins phosphorylate p53, stop it being degraded (only synthesised) and activate it
p53 binds to target genes incl key gene p21 - cdk inhibitory protein(CIP). This protein (made from p21 gene) recognises and binds to cdk-complex, inactivates it so it can’t phosphorylate its target genes
ie p21 is a brake the cell can put on if there is dna damage
p53 is a
TF (regulating p21) and tumour supressor (when p53 gene is mutated often results in cancers)
cell cycle withdrawal
cells can exit the cell cycle and go into a G0 state- resting
Some stay there and never proliferate again, others wait to receive cues to go back into cell cycle
Average rate of cell division varies based on
cell type
Quiescent cells
Have withdrawn into G0 but have the capacity to re-enter the cell cycle (proliferation), cued by right signals
This involves regulation of the G1/S phase checkpoint by the retinoblastoma (Rb) protein
G1
cell contents, excluding chromosomes are duplicated
S
46 chromosomes duplicated
G2
cell double check the dupl chromosomes for error making any needed repairs
Control of cell proliferation by Rb
Holds onto TFs that activates genes that are involved in G1 to S transition
Various local signals can regulate this cell cycle control
Signal comes in and triggers intracellular signalling pathway
Results in accumulation of activated G1/S-Cdk, which (in S phase) phosphorylates Rb- changes conform (to become inactive) to release TFs which bind to genes required to initiate process of cell proliferation
Mitogen signals
Promote cyclin synthesis and KIP/CIP degradation
Terminal differentiatied cells
can be considered to be in a specific form of G0 state
Permanent withdrawal from the cell cycle
different to quiescent cells
examples of terminally differentiated cells
neurones
keratinocytes in skin
Goblet (secretory) and enterocytes (absorptive)
Gut epithelial cells
Senescence
for a normal cell, limit to number of times cell can divide (stem cells exception cancer cells evade senescence and are immortalised/transformed)
Hayflick’s limit
human embryonic fibroblasts can only divide a finite number of times in culture
When normal cells lose the capacity to divide, what post-mitotic state do they enter
Cellular or replicative senescence
in body or culture
Contributing factors to senescence
Accumulation of KIPs/CIPs with more divisions- makes it harder to make enough active cyclin-cdk to go back into cell cycle
shortening of telomeres
telomeres
WR
cell number is a balance between
proliferation and apoptosis
