2.8 Cell Replication Flashcards
What is the cell cycle?
An orderly sequence of events in which the cell duplicates its contents and divides in two
What stages of the cell cycle make up interphase?
G1 + S + G2
What factors do different rates of mitosis depend on? CENTS
Complexity of system
Embryonic vs adult
Need for renewal of cells
Tumour
State of differentiation
Which cells never divide?
Neurons, skeletal muscle, hepatocytes
What does pre-mature, abnormal mitosis result in?
Cell death
Why is mitosis the most vulnerable period of the cell cycle?
DNA damage cannot be repaired, gene transcription is silenced, cell metabolism is low, thus cells are killed more easily
What is G0?
The quiescent phase
What state are the cells in when they are in G0?
The cells are not dormant, but non-dividing
What does the centrosome consist of?
Two centrioles at 90 degrees to one another
What is a centriole?
Barrels of 9 triplet microtubules which form the mitotic spindle
Where do the microtubules grow from on the centrosome?
Microtubules grow from the nucleating site on the centrosome
Microtubules are polymers of what?
Alpha and beta tubulin dimers
What is a kinetochore?
Protein complexes that assemble at the centromere of a chromosome and function to connect the chromosome to the microtubules during anaphase
In what phase of mitosis does the spindle attach to the kinetochore?
During metaphase
What happens to the microtubules during anaphase?
They get shorter as they pull chromosomes apart
In which phase d the spindle microtubules start to form?
Prophase
What occurs in the G1 phase of the cell cycle?
The cell makes mRNA and proteins in preparation for the next steps
What is aneuploidy?
An abnormal number of chromosomes
What is meant by syntelic attachment of the spindle?
When both kinetochores attach to spindles from one spindle pole, so the whole chromosome is pulled to one pole
What is meant by merotelic attachment?
When spindle fibres from two poles attach to one kinetochore
What occurs during the S phase?
Organelle replication and protein synthesis
What happens during the G2 phase?
Period of rapid cell growth in preparation for mitosis
What happens to cohesin during anaphase?
Cohesin breaks down
What occurs during telophase?
The daughter chromosomes arrive at the spindle and nuclear envelopes reassemble at each pore
What happens to chromatin during prophase?
Chromatin condenses
What is the function of a microtubule organising centre?
Forms the spindle fibers
How do we get cell growth? (Leaving G0 to G1)
Growth factors bind tyrosine kinase receptors in cell surface (mitogen signalling)
This triggers an intracellular signalling pathway, increasing protein synthesis and decreasing degradation, stimulating cell growth
What type of molecule is c-Myc?
A transcription factor and oncogene which is overexpressed in many tumours
What does c-Myc promote?
G0 to G1 transition
Which oncogene is over expressed in many tumours?
c-Myc
What two things can occur if something goes wrong with cell replication?
- Cell cycle arrest while DNA damage is being fixed
- Apoptosis (programmed cell death)
In the absence of a stimuli to progress into the next stage of replication, what happens to the cell?
Cells go into G0 phase (quiscent phase)
What does the exit from G0 phase require?
Growth factors and intracellular signalling cascades
What forms when cyclins bind to cyclin dependant kinases?
They form an activated cyclin-CDK complex
What do cyclin dependant kinases have to bind to in order to be activated?
Cyclins
Which Cyclin-Cdk complex leads to the progression into G1 phase?
Cyclin D - Cdk4/6 complex
Which Cyclin-Cdk complex leads to the progression into S phase?
Cyclin E - Cdk2 complex
Which Cyclin-Cdk complex leads to the progression into M phase?
Cyclin A - Cdk2 complex
Which Cyclin-Cdk complex is formed after M phase?
Cyclin B - Cdk1 complex
How are cyclins expressed through the cell cycle?
Transiently
How are cyclins switched off during the cell cycle?
They are made inactive by ubiquitylation - where ubiquitin molecules are added so the cell degrades the cyclin, thus inactivating the Cdk
What is retinoblastoma?
A tumour suppressor
How does retinoblastoma protein work?
Active Rb holds an inactive E2F transcription factor (that cannot turn on genes for cell cycle progression) and only releases it when Rb is phosphorylated
What phosphorylates Rb?
Activated cdk-cyclin complexes
What does mitogen signalling do to Rb, in a proliferating cell?
Mitogens activate intracellular signalling, leading to G1-Cdk and G1/S-Cdk complex production
The complexes phosphorylate the active Rb bound to E2F, inactivating Rb and releasing E2F
What does phosphorylation of Rb lead to?
Target genes needed for cell cycle progression (e.g. DNA polymerase, thymidine kinase) can now be activated
Describe how p53 works as a tumour suppressor?
p53 recognises damage to DNA
p53 is phosphorylated and activated
Activated p53 binds to p21 gene, activating transcription and translation
The p21 enzyme inhibits cyclin-cdk complexes, preventing phosphorylation of Rb thus the cell cycle cannot progress
What does p21 do?
Inhibits cdk-cyclin complex formation, preventing the phosphorylation of Rb
When does Cdk activity peak?
During mitosis
What does c-Myc induce the expression of?
Cyclin D
Why is cyclin D so important?
Entry to the cell cycle requires Cyclin D
What two checkpoints can occur in the G1 phase?
Check for damaged DNA
Check for unfavourable extracellular environments
What checkpoints can occur in the S and G2 phase?
Check for damaged or incompletely replicated DNA
Why are checkpoints needed in the cell cycle?
The cell can pause at checkpoints to repair DNA or undergo apoptosis if DNA is unrepairable
This prevents passing on of damaged DNA to progeny, preventing cancer
What can induce a checkpoint in mitosis?
Check for chromosomes improperly attached to the mitotic spindle
What do protein kinase cascades lead to and why?
Signal amplification, diversification and an opportunity for regulation
Since the activity of kinases is regulated by phosphorylation (by other kinases) and dephosphorylation (by phosphatases)
Why are protein kinases useful for cell cycles?
Since the protein kinases can be turned on and off, it is very helpful in regulating the progression through the cell cycle
What actually activates Cdks?
When the cyclin binds to Cdk, the complex is still inactive
The complex has to be phosphorylated with both inhibitory and activating phosphates
Once the inhibitory phosphate is removed by protein phosphatase, the complex is activated
What removes inhibitory phosphates from the Cdk complexes in order to make it active?
Phosphatase
How does positive feedback in the Cdk-cyclin system work?
The active Cdk complexes then activate more phosphatases so more inhibitory phosphates can be removed from the inactive complexes, leading to more activation of complexes
During ubiquitination, what do cyclins get degraded into?
Amino acids
How might over expression of c-Myc lead to aberrant cell cycling and cancer?
Inappropriate entry into G1 – S phase
How are Cdks rendered active to allow progression to the next phase of the cell cycle?
- Binding of cyclins
- Phosphorylation
- Dephosphorylation
How are active Cdk-cyclin complexes rendered inactive to allow orderly progression to the next phase of the cell cycle?
Degradation of cyclins
How can p53 rapidly respond to DNA damage?
p53 protein is continuously made and degraded
What oncogenes are mutationally activated or over expressed in breast cancers?
EGFR/HER2
Cyclin D1
How does herceptin antibody treat HER2+ metastatic breast cancer?
It blocks HER2 signalling and stops uncontrolled cell proliferation
What tumour suppressors are relevant in the cell cycle?
Rb – loss of function mutations in 80% of small cell lung cancers
p53 – loss of function mutations in 50% of all cancers
