MBC - Cell Replication Flashcards
Where do cells arise from?
Pre-existing cells
What are the three stages of the cell cycle?
Growth and chromosome replication
Chromosome separation
Cell division
In what scenarios will cells divide at different rates?
Embryonic vs adult cell Complexity of system Necessity of replication State of differentiation Tumour cells
How does necessity for replication affect cell division?
E.g. intestinal epithelial cells replicate in 20 hours due high necessity, but hepatocytes replicate every year due to low necessity
How does state of differentiation affect cell division?
E.g. neurones and cardiac myocytes are specialised cells that don’t divide
How do tumour cells affect division?
Tumour cells undergo very quick and uncontrolled division
What is the correct order of phases for the cell cycle?
G1, S, G2, Mitosis, Cytokinesis
What phases are involved in interphase?
G1, S, G2
What is another name for G0?
Quiescent phase
What can a cell do before going to S phase from G1 at the cell checkpoint?
Either progress into S phase or withdrawn to G0.
Is the cell dormant in G0?
No - it is just not dividing
What decides the fate of cells in G1?
Cells in G1 need a stimulus to progress into S phase, without a stimulus the cells will withdraw into G0
How do cells in G0 go to S phase?
Cells need a stimulus which will take them back to G1 and then S phase afterwards.
What is the significance of the checkpoint before S phase?
The checkpoint allows the cell to see if the external environment is favourable:
Are there enough nutrients and growth factors?
If a cell is trying to enter mitosis from G2 but reversible DNA damage is detected at the checkpoint, what happens?
The cell will pause at the checkpoint and will attempt to repair DNA damage.
If DNA damage at a checkpoint is irreversible, what happens?
The cell will undergo apoptosis
How does the cell respond to growth factors in the external environment?
The cell has tyrosine kinase (growth factor) receptors which bind to external growth factors which are present in a favourable environment
What is the purpose of MAP kinases?
These are used in an intracellular signalling pathway to amplify the signal and increase protein synthesis/decrease protein degradation, causing cell growth.
What are examples of MAP kinases?
Ras
ERK
What is c-Myc?
Transcription factor - drives the production of specific genes.
What does c-Myc do?
Stimulates the expression of cell cycle genes which allow the cell to progress from G0 to G1
How and why does c-Myc concentration change?
It increases in response to growth factor addition to allow progression of the cell cycle
What is the relevance of c-Myc and cancer?
c-myc is an oncogene and is overexpressed in many tumours
What are cyclin dependent kinases?
Family of regulatory proteins essential for cell growth/division
Where are CDKs found?
Present in proliferating cells
When do CDKs become active?
When bound to cyclin (+other factors)
How does CDK concentration fluctuate?
It doesn’t
What do CDKs phosphorylate?
The hydroxyl group on serine, tyrosine or threonine residues.
Does cyclin concentration change in the cell?
Yes
When does CDK activity peak?
When cyclin production peaks
How does c-Myc affect entry into the cell cycle?
c-myc causes production of cyclin D, which then forms a CDK 4/6 complex with cyclin D for cell cycle entry
Explain, using kinase 1 and kinase 2, the concept of protein kinase cascades?
Kinase 1 is off however phosphorylation turns it o, allowing the phosphorylation of kinase 2 and thus turning it on, this then repeats for many different proteins down a cascade.
What does protein kinase cascading allow for?
Signal amplification
Diversification (multiple pathways can get involved)
Regulation of cell cycle progression
What do phosphatases do?
Reverse the effects of phosphorylation thus turn off the kinases
What are the 4 CDKs?
1,2,4,6
What are the 4 Cyclins?
D,E,A,B
How is CDK activity regulated?
CDKs require cyclin interaction and phosphorylation for activation
How are cyclins expressed?
Transiently at specific points in the cell cycle, then they are degraded.
What is the first step of active Cyclin-CDK complex formation?
Inactive CDK interacts with cyclin to form inactive complex.
What is the second step of active Cyclin-CDK complex formation?
Inactive complex is then phosphorylated by protein kinase, adding a inhibitory and an activating phosphate group. Still inactive
What is the third (final) step of Cyclin-CDK complex formation?
Inactive complex is ridden of inhibitory phosphate via activating protein phosphatase to result in an active complex.
How does positive feedback increase the level of active Cyclin-CDK complex?
Active CDK complex acts as a kinase to phosphorylate the inactive phosphatase cdc25. This leads to an increase in active cdc25 which in turn phosphorylates inactive complex to form active complex.
How are cyclin-CDK complexes turned off?
Ubiquitination: leads to cyclin destruction and thus complex deactivation
How do cyclins give directions and timing to the cell cycle?
c-Myc gives rise to cyclin D/CDK 4/6
This in turn stimulates expression of cyclin E, then A and b respectively.
Why do we have cyclical activation?
As cyclins can be degraded
What is the Rb gene?
Tumour suppressor gene that acts as a molecular brake
What happens when Rb is missing or inactive?
We develop cell cycle progression problems and thus a retinoblastoma (eye tumour)
How does Rb stop cell proliferation?
Active Rb sequesters/holds transcription factor E2F in an inactive state which normally increases expression of cell cycle proteins e.g. thymidine kinase and DNA polymerase.
How does Rb allow cell proliferation?
When a growth factor binds to a mitogen receptor, intracellular signalling leads to G1/S-CDK complex which phosphorylates active Rb to inactive Rb, releasing E2F and allowing cell cycle progression.
What is p53?
Tumour suppressing gene that arrests cell with damaged DNA in G1.
What does p53 do?
When there is DNA damage, p53 will activate protein kinases to arrest the cell
What happens with p53 in the absence of DNA damage?
p53 is degraded in proteosomes
What is the advantage of initially making p53 regardless of DNA damage?
p53 can be rapidly activated to arrest the cell before further cell cycle progression if there’s DNA damage
What happens with p53 when there’s DNA damage?
Protein kinases are activated and activate/stabilise p53 with phosphorylation (addition of phosphate). p53 then binds to regulating region of the p21 gene to express p21.
What is the p21 translation product?
CDK inhibitor protein
What does the CDK inhibitor protein from p21 do?
It deactivates the active G1/S-CDK complex to stop cell cycle progression, stopping the cell cycle of a cell with damaged DNA.
What are 5 example oncogenes?
EGFR/HER2
Ras
Cyclin D1
c-Myc
What are EGFR/HER2?
Oncongenes that are mutationally activated/overexpressed in breast cancer. E.Herceptin antibody is used in treatment of HER2+ metastatic breast cancer.
What is Ras?
Oncogene that is mutationally activated in many cancers.
What is cyclin d1?
Cyclin that is overexpressed in 50% of breast cancers
What is c-myc (oncogene)?
Oncogene that is overexpressed in many tumours.
