Flashcards in The Cell Cycle Deck (41)
Know the cell cycle
Starts with Mitosis, then G, then the S phase where chromosome replicate and then is the G2 phase.
Other than the S phase, we have interphase.
What are Mitogens
In order for the cell to grow or proliferate the cell has to have a signal, these are called mitogen, their receptors are called mitogen receptors.
Mitogens control cell cycling by acting on the G1 phase of the cell cycle
How does mitogens induce signaling
They do this by the growth factor mechanism. The receptor is phosphorylated at the intermembrane space, interacts with GRB2-SOS which then induces the RAS to binds to GTP which then induces the MAP kinases to initiate signaling
What does the MAP kinases do in this signaling
They induce gene regulatory proteins such as Myc. This is often over expressed in cancer. He said now we enter G1 phase
What happens before the cell goes to the next stage of cell cycle after G1
It checks if it has enough glucose and if it has the right ratio of ATP to AMP.
Fatty acid and glycogen synthesis is turned off.
What happens in G1
The cell basically gets bigger. This is the longest phase of the cell cycle. The following happens:
1. Cellular energy level is high
2. Increase protein synthesis
3. Increase ribosome production
4. Some organelle duplication
5. Increase in cell size
What controls this desire to get bigger
Protein complex called mTORC. it is a big kinase complex but it also has the ability to sense nutrients. It senses free fatty acids and glucose in the environment and when there is plenty it is turned on and increases the rate of protein synthesis.
It activates ribosomes and elongation factors.
What happens after G1
We make DNA`
What are licensing factors
Proteins required to assemble the DNA helicase complex at ORC such as cdc6 and cdt1
What is necessary for the licensing factors to allow DNA replication
They have to be phosphorylated to be in active form and allow replication of the DNA
What happens to licensing factor? When are they made and when are they destroyed
They are made in early G1 phase and they are removed or destroyed in the M phase
What does geminin do
It binds to the licensing factors (cdt1) and inhibits them. It is highest in the S phase. Remember that the conc. of cdt1 increases in the G1 phase and keeps on increasing throughout the G1 phase and starts to decrease as the S phase starts.
Also the concentration of cdc6 increases as towards the end of G1 phase and keeps on increasing until the END OF S phase.
Geminin concentration increases in the S phase as it is an inhibitor of cdt1.
What protein complex forms during the S phase
The DNA is wrapped up in the S phase into a protein complex called the Cohesion complex. It wraps around the newly synthesised DNA. It acts as a cage.
When is the cohesion protein complex broken down
What happens in G2 phase
It check things, is DNA made? is it made correctly? Is the cell big enough?
If there are errors in DNA, they are corrected with the help of PARP.
How are cell cycles regulated
Cyclins, and with protein dependent cyclins kinases.
What are the positive and negative cell cycle regulators
Positive are cyclins, cyclin dependent protein kianses (CDK) and protein degradation.
Protein degradation actually promotes the cell to go the next cell cycle.
Negative regulators are Transcriptional repressors, CDK inhibitors and check points.
What are cyclins
Protein expressions cycle, they go up and down in a cell cycle, they are CDK substrates.
On the slide it said cyclins are important REGULATORS of CDK, their conc. goes up and down in a cell cycle
How is the G phase promotion regulated
In the cell initially there are CDK4 and CDK6 present that are not doing anything. The cell makes Cyclin D that binds to CDK 4 and 6. This activates 4 and 6 that go on and p's things. This leads to promotion of the G1 phase. When the cell is ready for S phase there is a check point.
What is the check point for S phase
The cell makes Cyclin E which activates CDK 2. This commits the cell to replicate DNA and go on to the S phase. CDK2 phosphorylates p27 (I don't think we need to know that).
What is involved in the progression of S phase
Degradation of cyclin E and making of cyclin A. Cyclin A also binds to CDK 2 and keeps it turned on during the S phase.
Cyclin A stimulates chromosome duplication (unlike cyclin E that initiated DNA replication)
What happens when you come near M phase
Cyclin A lasts through the G2 phase. As we near the M phase the cyclin A is degraded and we make another substance called Cyclin B. This activates CDK1. This allows entry into the M phase. it drives the cell through the M phase
What is the added check point of CDK1 that leads to mitosis
CDK1 when it binds to cyclin B is still off becuase it has inhibitory p's on it. It is only activated after it is dephosphorylated by CDC25 (it is a phosphatase). This activated cdk1 leads to activation of more cdc25 which then activate more cdk1s (positive feedback loop).
What are the functions of CDK1.
There are 4.
1. Assembly of mitotic spindle
2. Chromosome condensation
3. Nuclear envelope breakdown
4. Actin cytoskeleton rearrangement
What is the 3rd check point for CDK1
p27 which is an inhibitory protein for CDK1. Even when the CDK1 is fully active p27 can bind to it and completely inhibit its activity
How is cyclin B destroyed after the M phase
By the process of ubiquitinylation
What is the role of Ubiquitin ligases (E3s) in cell cycle regulation
There are 2 main complex, SCF and APC/C. SCF is active at late G1.
Know that these complex consist of a catalytic site, a scaffolding protein site and a variable site, so there are several different types of these complexes.
How does SCF complexes play a specific role in cell cycle regulation
The SCF complex can identify CDK inhibitors that have been phosphorylated, these p's groups are identified by the SCF complex and it puts a ubiquitin tag on them so these inhibitors are then chewed up by the proteosome. The cell can then go to the next cell cycle
How does the APC/C complex play a role in cell cycle regulation
The activating subunit of APC/C binds to it, activating APC/C. This APC/C binds to the cyclin B, puts a ubiquitin tag on it and then cyclin B is destroyed by the proteosome.
What is an APC
It is a ubiquitin ligase
What is separase
It is a protein that breaks down the cohesion complex.
How is separase activated
By release of secruin
What is the role of APC relating to separase
It puts a ubiquitin tag on its activating unit securin and gets it destroyed
How does APC regulate cage breakdown
APC is activated, it puts a ubiquitin tag on securin, securin gets destroyed, separase is now active and it breaks down the cohesion complex.
What does mTOR senses
Glucose, mitogens and branch chained amino acids
What does mTOR do
It p's some TF and other things to allow progression through G1
What does DNA damage does to you in late G1 phase, G2 phase or at M phase
DNA damage activates ATM/ATR kinase. These kinases can p's p53 to stabilize it which arrests the cell in that cell cycle. The DNA repair mechanism kicks in to fix the DNA damage and the cell can then go back to its normal cycle
What is MAD2
It is a diffusable protein.
Explain the S/G1 phase check point
We have a RB protien that basically inhibits S phase gene transcription. When the Cyclin D is made in G1 phase it p's Rb so it is slightly less active now but still supresses gene transcription.
Towards the end of G1 phase the cell makes Cyclin E which causes complete p's of Rb. This causes complete p's and inactivation of RB, gene trasncription for S phase can now be initiated and the cell is now able to enter the S phase
Rb is for retinoblast.
Rb is bound to HDAC
What happens in cervical cancer
The viral protein leads to the degradation of Rb which causes development of cancer