CELL CYCLE Flashcards
Normally, cells do not proliferate unless stimulated by what:
Extrinsic factors
What are the potential decisions of a cell?
Quiescent (G0)
Proliferate
Differentiate
If there is an overriding issue, what happens to the cell cycle?
Can be halted.
A mixture of signals has to be integrated by the cell to make the decision as to what the cell is going to do. What in the cell nucleus makes the major decisions?
The cell cycle clock
What mixture of signals has to be integrated by the cell for the cell to be able to make a decision?
Tyrosin kinase receptors GCPR TGF beta receptors Integrins Nutrient status
What are the phases of the Cell Cycle?
G0 - quiescent state
G1 - CDK4/6 must associate with cyclin D’s. In this phase, the cell grows in preparation fro DNA replication and certain intracellular components undergo replication. At the end of G1, E cyclins must associate with CDK2 to progress into S phase.
S - A type cyclins bind with CDK2. S phase is where DNA is replicated. Later in S phase, A type cyclins bind with CDK1
G2 - B cyclins replace A cyclins binding with CDK1. In G2, there is rapid cell growth and protein synthesis.
M - B cyclins with CDK1 triggers mitosis
What are the 2 major control factors of the cell cycle?
- Binding of cyclins with cyclin dependent kinases
2. Cell cycle checkpoints
Why does collapse of cyclin levels occur as the cell progresses through the cell cycle?
Degradation of specific cycle levels allows for unidirectionality.
Why are D cyclins not the same as others?
They are controlled by extracellular signals.
At what point does the cell cycle become cell autonomous?
At R point
What are CDKs inhibited by?
CDK inhibitors
What CDK inhibitors inhibit cyclin D?
p16INK4A
p15INK4B
p18INK4C
p19INK4D
What CDK inhibitors inhibit other cyclins?
p57KIP2
p27KIP1
p21CIP1
What are the cell cycle checkpoints?
R checkpoint - is the cell big enough, is the environment favourable, is there DNA damage.
G2 checkpoint - is all DNA replicated, is the cell big enough, is the environment stable?
M checkpoint - are all the chromosomes aligned on the spindle?
What does DNA damage activate?
p53
Describe G1/S Restriction Point Progression.
CDK4/6 and Cyclin D form a complex that phosphorylate pRb bound to E2F. Build up of Cyclin E binds to CDK2 which hyperphosphorylating pRb freeing E2F to transcribe driving the cell into S phase.
When is DNA damage detected and what are the methods of repair.
The three checkpoints (G1, Entry to S phase, Entry to mitosis) are the sites of detection and arrest of the cell cycle.
There are two types of DNA repair in this case: non homologous end joining (G1) and homologous recombination (G2).
How is the cell cycle arrested upon detection of DNA damage?
DNA damage detected
ATM (double stranded breaks) and ATR (for single stranded breaks) are activated and associate with the site of damage.
Other kinases are activated such as Chk1
This causes phosphorylation of p53
p53 activates p21 gene coding for CKI to arrest the cell cycle
If DNA repair is incomplete then what occurs?
Apotosis will be triggered.
What does the combination of p53 and Mdm2 mean for a cell?
Ubiquitylation and degradation of the cell
If p53 is phoshporylated and as a result Mdm2 cannot bind to p53, what occurs?
active p53 binds to the regulatory region of p21 gene to transcribe for cyclin dependent kinase inhibitors to arrest the cell cycle.
What is the purpose of the p21 gene being transcribed?
Arrest of the cell cycle to allow time for DNA repair to take place.
If repair cannot take place then apoptosis will take place.
In G1, if the environment is not favourable or if there is an issue, what can occur?
The cell can make the decision to revert back to G0.
Deregulation of R point decision making machinery accompanies what?
Formation of most types of cancer cells.
What are the two important things that must occur is S phase?
- The DNA must be replicated accurately to prevent mutations.
- The DNA must only be copied once.
What is licencing?
It is the process that occurs in G1 where inactive helicases are loading onto the replication origins, forming a PreRC complex.
What happens to the PreRC complex after G1?
Helicases are activated in S phase by the S phase cyclin/CDK complexes and DNA is replicated.
Is the cell cycle always the same?
No.
Throughout different types of cells ie fibroblasts, ESCs there are differences in cyclin levels. Even throughout life, the inclination of cell cycles change ie early cells are inclined to apoptose if there is an issue rather than arrest and repair.
