Cell Replication Flashcards
What are the 3 main parts of the cell cycle?
- Cell growth and chromosome replication (size doubles) —> G1, S, G2 (interphase)
- Chromosome separation —> M
- Cell division —> cytokinesis
How often to hepatocytes divide?
Every year
How often to intestinal epithelial divide?
Every 20 hours
Which 2 cells never divide?
- Neurones
- Cardiomyocytes
What are the 5 phases of the cell cycle in order?
- G0
- G1
- S
- G2
- M
What is the G0 phase?
Quiescent phase —> cell not dividing
What is cytokinesis and when does it occur?
- Cytoplasm dividing
- Between M and G1
When are cells in G0?
No stimulus to divide —> not dormant but not dividing
What is required in the external environment for the cell cycle to stay stable?
- Correct nutrients (proteins, DNA bases, amino acids)
- Growth factors
What are the 4 stages of signalling cascades stimulating cells to leave G0?
- Response to extracellular factor (eg. growth factor)
- Signal amplification
- Signal integration/modulation
- Ras/Raf/MEK/ERk (kinases) phosphorylate
What happens if an issue is detected at a checkpoint? (2)
- DNA repair
- Apoptosis if unfixable
Which transcription factor is expressed to move a cell from G0 to S?
c-Myc
What is seen regarding c-Myc in tumours?
Over-expressed —> c-Myc gene becomes oncogene
Which enzymes drive a cell through the cell cycle?
Cyclin-dependant kinases (Cdks)
Which cells are Cdks present in?
Proliferating cells
When are Cdks active? (2)
- Cyclin is bound
- Phosphorylated correctly
Which 3 amino acids allow Cdks to be phosphorylated and why?
- Serine
- Threonine
- Tyrosine
All have hydroxyl group so can undergo phosphorylation
What is important about cyclins? (in name)
Produced and degraded in a cycle
Which specific Cdk-cyclin complex is required for a cell to enter the cell cycle?
Cdk 4/6-cyclin D
What are the 4 stages required for a cell to leave G0 and enter S?
- Growth factor stimulates…
- C-Myc (TF) production which stimulates…
- Cyclin D production which is part of…
- Cdk 4/6-cyclin D
What are the 5 key checkpoints in the cell cycle?
- G1 middle
- G1 end
- S end
- G2 middle
- M end
What is the 1st G1 checkpoint checking?
No DNA damage
What is the 2nd G1 checkpoint checking?
Extracellular environment
What is the S checkpoint checking?
No DNA damaged/poorly replicated
What is the G2 checkpoint checking?
No DNA damaged/poorly replicated
What is the M checkpoint checking?
Chromosome properly attached to mitotic spindle
How do protein kinase cascades work?
Activated kinase stimulates next kinase to activate
How is phosphorylation reversed?
Phosphatases
Why are signalling cascades important for the cell cycle? (3)
- Signal amplification
- Diversification
- Regulation
What are the 4 important Cdks for the cell cycle?
1, 2, 4, 6
What are the 4 important cyclins for the cell cycle?
A, B, D, E
What are the 3 steps of Cdk activation?
- Cyclin binds to Cdk —> Cdk-cyclin complex
- Phosphorylation —> inhibitory and activating phosphate groups added to Cdk-cyclin complex by protein kinases
- Dephosphorylation —> inhibitory phosphate group removed by activating protein phosphatase
Why does Cdk activation continue? (2)
Positive feedback
1. Active Cdk-cyclin inhibits Cdk-inhibitory kinase —> dec addition of inhibitory phosphate group
2. Active Cdk-cyclin activates more phosphatase via phosphorylation —> inc removal of inhibitory phosphate groups
When are Cdk-cyclin S complexes active?
S + G2
When are Cdk-cyclin M complexes active?
M
How are cyclins turned off?
Ubiquitination
What are the 2 steps of cyclin ubiquination
- Ubiquitin protein attaches to cyclin of active Cdk-cyclin —> marks cyclin for proteasome
- Proteasome binds cyclin —> cyclin destroyed —> Cdk inactive
How are Cdks activated unidirectionally and at the right time?
Active Cdk-cyclin stimulates expression of gene producing next cyclin —> activates next Cdk
What are the 4 Cdk-cyclin complexes activated throughout the cell cycle and when are they active?
- Cdk4/6-cyclin D —> end of G1
- Cdk2-cyclin E —> G1 to S
- Cdk2-cyclin A —> S to M (metaphase)
- Cdk1-cyclin B —> M (prophase to metaphase)
What is a retinoblastoma?
An eye cancer primarily affecting children
What causes a retinoblastoma?
Tumour suppressor protein Rb missing/inactive
Where is Rb found and why?
In all nucleated cells
- controls exit and entry to cell cycle
What is the function of mitogen?
Growth factor
- Drives protein synthesis
- Inhibits protein degradation
What is the function of Rb and how does it do this?
Stops cell proliferation
- Active Rb sequesters E2F transcription factors in inactive state —> genes for cell cycle progression not turned on
How can Rb be inactivated and which Cdk-cyclin complexes do this?
Phosphorylation
- G1-Cdk and G1/S-Cdk
What happens when Rb is phosphorylated?
- Inactivated —> transcription factors released —> cell cycle genes activated (DNA polymerase and thymidine kinase)
What are E2F family members and what do they do in the cell cycle?
Group of transcription factors
- Stimulate expression of genes producing cyclins
Which protein prevents cells with damaged DNA leaving G1?
p53
What is p53?
Tumour suppressor protein —> controls cell entry to S phase
What does activate p53 stimulate the production of and how?
p21
- binds to regulatory region of p21 gene
How does p53 prevent cells with damaged DNA leaving G1? (4)
- Damaged DNA activates protein kinase
- p53 phosphorylated by protein kinase —> activated
- p53 binds to regulatory region of p21 gene —> p21 produced
- p21 binds to Cdk-cyclin complex —> inactivated —> cell can’t progress through cycle
What is p21?
Cdk inhibitor protein
Which 4 proteins from oncogenes are over-expressed in breast cancer?
- EGFR/HER2
- Ras
- Cyclin D1
- C-Myc
What is the treatment for HER2+ metastatic breast cancer?
Herceptin antibody
Which tumour suppressor proteins cause small cell lung cancers when mutated?
Rb (80%)
Why is understanding p53 function so important in oncology?
Mutations cause most cancers
