Lecture 10 - Rb and Control of the Cell Cycle Clock Flashcards
What is the cell cycle clock? What does it control? What happens when a restriction point is passed?
The cell cycle clock is a mechanism that describes the lifecycle of a cell and controls the highly programmed events that lead the cell into and through DNA replication and cell division.
Once a restriction point is passed, the cell commits itself to the events of the next phase.
What are the 5 phases of the cell cycle and what do they represent?
1 - Go phase: nothing, stasis, due to lack of growth factors or presence of growth inhibitors.
2 - G1 phase: growth of cell, nutrient uptake, represents majority of cell life-span.
3 - S phase: DNA replication occurs
4 - G2 phase: nothing really works since cell is diploid (4N) and is crowded. Replication of cell machinery in preparation of division.
5 - M phase: mitosis/cell division
What are the five stages of mitosis and what do they represent?
1- Prophase: spindles form, DNA condenses
2 - Prometaphase: nuclear envelope breaks
3 - Metaphase: chromosomes line up at metaphase plate
4 - Anaphase: chromatids separate
5 - Telophase: nuclear envelope reforms
Where is the cell when it is first formed? How does it decide to proceed into the cell cycle?
When a cell is first formed, it is in the G1 phase. It must decide whether or not to proceed with the cell cycle using mitotic growth factors.
If a cell does not wish to go into G1, it will go into stasis in Go.
What/where are the four cell cycle checkpoint found? What do each control? Explain using a clockwise metaphor.
1 - End of G1 phase checkpoint: looks for DNA damage. If genome is impaired it will block S phase.
2- Middle of S phase checkpoint: looks for DNA damage. If genome is impaired it will block DNA replication.
3 - End of G2 phase checkpoint: looks to see if DNA replication is completed. If not, it will block entrance to M phase.
4 - Middle of M phase checkpoint: anaphase is blocked if chromatids are not properly assembled on mitotic spindle.
Why is G1 such an important phase? Why is the restriction checkpoint so interesting here?
The G1 phase is very important because if a cell leaves G1 it essentially commits itself to moving through the rest of the cell cycle.
The R-point at the end of G1 is so interesting because it is highly variable and sensitive to internal and external environmental conditions.
Once a cell passes this R-point, the cell has commited to division and proliferation and if it is messed up/mutated… this can be bad.
In very common cancers, cells are found to have been allowed past the G1 R-point and have proliferated when they shouldn’t have. During the G1 phase, cells respond heavily to mitogenic growth factors as well as TGF-beta.
What are additional checkpoints? Give some examples.
Additional checkpoints can halt the cell cycle if something is not as it should be in relation to the cell.
This can include nutrient supply, disruption of connection to ECM, or DNA/physical damage to the cell. In the majority of cases, apoptosis occurs quickly following the failure of such an additional checkpoint.
What are CDKs? What are the five major CDKs involved in the Cell Cycle and where are they found?
CDKs, or cyclin-dependent kinases, switch on/off various proteins involved in the cell cycle progression. These kinases include serine and threonine, and they phosphorylate target proteins for their desired effects.
CDKs are regulated by cyclin proteins, and each CDK has an associated family of cyclin.
Five major CDKs in the Cell Cycle:
1 - middle G1 phase: D CDK4/6 (cored) 2 - end of G1 phase: E CDK2 (full) 3 - early S phase: A CDK2 (full) 4 - late S/early G2 phase: A CDC2 (full) 5 - middle M phase: B CDC2 (full)
Why are D-type cyclins so important?
D-type cyclins act/fluctuate through the G1 phase which covers most of the cell’s life-span. They are strongly influenced by environmental factors. All D-type cyclins bind to CDK 4/6 and are associated with the transcription factor C/EBP-beta (important for differentiation).
What is so awesome/efficient about Cyclin-CDK’s? How do they implement a somewhat unidirectional path to the cell cycle?
Cyclin CDKs stimulate the production of the subsequent cyclin that is to replace them.
Ex: a D CDK4/6 whill cause the synthesis of a E CDK2
How is the CC controlled by CDK inhibitors?
Give one example.
CDK inhibitors inhibit ATP binding to CDK and reduces affinity for cycling-CDK association.
Ex: p27Kip1 inhibits the S, M, and G2 CDK-cyclin complexes
How is the CC controlled by TGF-beta
TGF-beta receptor ligand binding directly causes P15INK4B (semi-shell) to inhibit the D-cyclin complexes, while weakly influencing the p21Cip1 (small square) to inhibit the E, A, B cyclin complexes.
How is the CC controlled by Extracellular Signals?
Extracellular signals recieved by an RTK receptor and mitogen ligand (example)
Effects concentrations and nuclear localization of CDKIs. Messes them up.
Causes P21Kip1 (small square) and p27Kip1 (oblong T) to translocate to the cytoplasm, pulling and inhibiting A, B, E cyclin complexes.
Essentially, Mitogenic signals prevent CDKIs from entering the nucleus.
Do different CDKIs effect different cyclin-CDKs in different ways? Give an example.
Yes, they do.
Example: p21Cip1 and p27Kip1 inhibit A, E, and B cyclins… but STIMULATE D cyclins
How does the different effects of CDKIs explain the cell cycle?
As more and more D cyclins are stimulated by p21Cip1 and p27Kip1, more and more are produced that take them up (positive feedback loop).
Eventually, with enough D cyclins present, the inhibitors of A, E, B cyclins are used up in the D cyclins leaving the other cyclins free to move along the cell cycle.
