Cell Replication Flashcards
3 components of the cell cycle
Duplication
Division
Co-ordination
5 factors that affect cell division
Cell maturity
Complexity of system
Necessity for renewal
State of differentiation
Tumourigenesis
Cell maturity
Embryonic cells divide at a faster rate than adult cells ; most mammalian mature cells can divide every 24 hours
Complexity of system
Higher system complexity the LOWER THE RATE of expected division ; yeast cells take 1.5-3 hours
Necessity for renewal
Cells with high turnover like intestinal epithelial cells divide at a faster rate than hepatocytes (once every year)
State of differentiation
Neurons and cardiac monocytes are terminally differentiated so will never divide
How are terminally mature cells repopulated
By stem cells and progenitor cells
Tumourigenesis
Loss of all control elements governing cell cycle ; tumours have uncontrollable fast rate of division
Interphase
G1 S G2
M phase
Mitosis + cytokinesis (cytoplasmic splitting)
G phases
Gap phases - prepping for S (by growing in size + synthesising proteins) OR prepping for M (by growing in size and checking/repairing DNA)
S phase
Synthesis phase
G0
Quiescent - takes urself out of cell cycle ; terminally mature cells - if cells need to quiesce (rest) they can enter G0
How does G0 work?
Cell must have necessary resources to endure replication of 3.2 B base pairs/double in size ; so if no stimuli present most differentiated cells go into G0 phase
What about cells in G0 phase
They are simply non-dividing ; neurons/skeletal muscle/hepatocytes
Monitoring of external environment includes
Ample nutrients + ample growth factors
Checkpoints in cell cycle
3 checkpoints - G1 checkpoint to enter S phase ; is environment favourable?
G2 checkpoint to enter M - has DNA replicated correctly/not damaged
M checkpoint - are all chromosomes properly attached to mitotic spindle
Pause process?
IF CELL HAS TO UNDERGO DNA REPAIR
Cell pauses at checkpoint to allow DNA repair to occur ; if DNA beyond repair cell leaves cell cycle + undergoes apoptosis
Why do cells enter G0 phase?
Differentiation - specialised cell types do not divide until needed for tissue repair etc
Senescence - may lost its ability to divide but still remain metabolically active ; can result from aging/cellular stress/DNA damage/oncogenes signals
Cell quiescence - resting cells to conserve energy (until activated for growth/repair)
Terminal maturity - neurons/muscle/mature RBCs - PERMANENTLY post-mitotic in G0
External signals - lack of growth factors/nutrients signals from neighbouring cells
DNA damage - time needed for repair mechanisms
Cell stress - protective mechanism in oxidative stress/heat shock/inflammatory signals etc
How do cells leave the G0 phase?
Through extra cellular stimuli (growth factors binding to receptor on cell surface membrane) which starts an intracellular signalling cascade
Growth factor binds to receptor which leads to intracellular signalling pathway causing protein synthesis to increase or protein degradation to decrease (either way leads to CELL GROWTH)
Signal cascade also known as
Signal amplification ; cascades can modulate various other cascades in parallel - signal integration/modulation by other pathways - causes cell to enter cell cycle from G0
c-Myc
Is a type of growth factor called a transcription factor which expresses a particular gene ; promotes transition of cell out of G0 into G1
ONCOGENE - over expressed in many tumours (cell will be going into replication when conditions are not favourable)
Why are serine threonine and tyrosine all sites of phosphorylation?
They all contain hydroxyl groups in their side chains so can be phosphorylated by kinases (just like glucose)
Idk levels during cell cycle?
Really do not fluctuate
How do cdks work?
Only active when a cyclin is bound to it (but cdks are present in all proliferating cells)
Cyclin fluctuations?
Their greatest concentration matches the optimum levels of cdc during the mitotic phase (cyclin conc simply rises during interphase)
Cdk activity during interphase
Practically non-existent
Cyclin concentration?
Fluctuates - it is cyclic as it is produced and then degraded after mitosis to be produced again
Growth factor drives what pathway?
Tyrosine kinase signalling pathway
At the end of that pathway?
Transcription factor c-Myc is present which turns on Cyclin D gene that cdk needs to drive the cell into S phase
cdk + phosphorylation….
Drives the cell into S phase
How does a kinase usually turn on?
It is phosphorylated ; that kinase can phosphorylate other kinases leading to an amplified intracellular response ; POTENTIAL FOR REGULATION
Phosphatases job?
Removal of the phosphates from those kinases will turn them off
Cyclins are —- expressed
Transiently
Sequential phosphorylation/dephosphorylation Cdks-4
Cyclin dependent kinase chilling by itself
Cyclin comes along but the acc cdk has an inhibitory and activating phosphate (which is getting phosphorylated)
Only will phosphorylate when an activating protein phosphatase comes along and removes that inhibitory phosphate
What also drives the cell cycle forward?
Positive feedback ; once you have your active Cdk which is phosphorylating it will phosphorylate many things such as the inactive phosphatase making it active (MASSIVE POSITIVE FEEDBACK)
What else can positive feedback do?
Active Cdk can also activate inhibitory kinase and inhibit the whole process
What is the term for constant degradation/turning signal systems on and off?
Progressive induction
Ubiquitination
Process by which many proteins are removed from the body ; a tag for a proteasome to degrade the protein its attached to (in this case the cyclin) - GENE INDUCTION
What is ubiquitination coupled with?
Proteosomal degradation
Exit out of different phases of cell cycle
Controlled by degradation of cyclins
Retinoblastoma
Gene product that acts as a molecular brake ; this is a tumour suppressor that is missing/inactive during tumour genesis
Mechanism of Rb
Active Rb sequesters a Transcription factor (in the E2F family) inactive so the TFs cannot turn on genes needed for cell cycle progression like DNA Polymerase or Thymidine kinase for S phase
How is this molecular brake released?
Activation of cyclin dependent kinases phosphorylates Rb which induce its inactivation causing a conformational change and for it to release TF which will bind to correct place in genome and turn on genes for DNA synthesis
Another tumour suppressor is
p53
p53 life cycle?
Constantly produced and degraded/turned over - process of ubiquitination
Mechanism of p53
x-rays cause DNA damage which leads to activation of protein kinases that phosphorylate p53 stabilising + activating it ; it is a TF that will bind upstream of p21 gene (needed when a cell is making DNA)
Oncogenes
Overexpressed resulting in tumour formation
EGF4/HER2
Over expressed in breast cancers ; Herceptin antibody for treatment of HER2 metastatic breast cancer
Ras
Mutationally activated in many cancers
Cyclin D1
Over expressed in 50% of breast cancer
C-Myc
Overexpressed in many tumours
Order of cyclin expression
C-myc promotes cyclin-D which upregulates cyclin E which upregulates cyclin A which upregulates cyclin B
When is cyclin D present
G1
When is cyclin E present
End of G1 going into S
Cyclin A
Middle of S going and stays till mitosis
When is cyclin B present
Start of mitosis till anaphase
What does p53 do
STOPS cell cycle from continuing
What is c-myc
Transcription factor which stimulates the expression of cell cycle genes (genes that synthesise cyclins)
