Carla - Regulation of the Cell Cycle Flashcards
What needs to be controlled?
(4)
The length of time the cell spends in each phase
The initiation of events in correct order
Ensure each event is only triggered once per cycle
A binary switch to trigger events completely and irreversibly - either on or off
How are checkpoints controlled?
There is negative control of checkpoints
The cell checks what hasn’t been done -> no positive signals stimulate
Why do we need checkpoints?
Cells would never replicate
Cells would never stop replicating
What three regulators are important at the checkpoints?
Cyclins
CDKs -> cyclin dependant kinases
Tumour suppressors
What are cyclins?
(3)
Core cell cycle regulators
Group of related proteins
Four basic types found in humans
What are the four basic types of cyclins?
G1 cyclins
G1/S cyclins
S cyclins
M cyclins
When do C1 cyclins peak?
Doesn’t really peak
Begins to raise at G1 phase and decreases back down by the M phase
When do G1/S cyclins peak?
The beginning of the S phase
When do S cyclins peak?
The G2 phase
When do M cyclins peak?
The M phase
How do cyclins work?
(2)
They drive the cell cycle forward by activating or inactivating target proteins inside the cell
They cannot work alone - they must be coupled with CDKs
What are kinases?
Enzymes that are able to phosphorylate
What does CDK stand for?
Cyclin dependent kinases
What are CDKs?
(3)
Large family of serine/threonine kinases
Dependent on cyclins
Different types are restricted to specific stages of the cell cycle
List four CDKs
CDK4
CDK6
CDK2
CDK1
What do CDK4 and CDK6 do?
They regulate the G1 stage
What does CDK2 do?
Regulates the transition of G1 to s phase
What does CDK1 do?
Regulates G2 and mitosis
Give four examples of cyclins
Cyclin D, E, A and B
What type of cyclin is cyclin D?
G1 cyclin
What type of cyclin is cyclin E?
S-phase cyclin
What type of cyclin is cyclin A?
S-phase and mitotic cyclin
What type of cyclin is cyclin B?
Mitotic cyclin
Write a note on cyclin D
(5)
Expression is induced by stimulation by growth factor, amino acids, hormones and oncogenes such as Ras
Partners with CDK4 and CDK6 in early to mid G1 phase
Phosphorylates and inactivates the cell inhibitory function of the retinoblastoma protein in cooperation with cyclin E/CDK2
Known to modulate local chromatin structure and transcription of genes involved in proliferation and differentiation through CDK-independent association with histone acetylases and deacetylases
Amplification/overexpression is seen in many cancers -> 45% of mammary cancers (mammary oncogene)
What induces the expression of Cyclin D1?
Expression is induced by stimulation by growth factor, amino acids, hormones and oncogenes such as Ras
What can Cyclin D partner with?
When does cyclin partner with these?
Partners with CDK4 and CDK6 in early to mid G1 phase
What does cyclin D partnered with CDK4 and CDK6 do?
Phosphorylates and inactivates the cell inhibitory function of the retinoblastoma protein in cooperation with cyclin E/CDK2
What does the retinoblastoma protein work with?
Cyclin E/CDK2
What happens when the retinoblastoma protein is inhibited/phosphorylated?
Normally it stops the cell from replicating but when phosphorylated replication can be started
What can cyclin D1 do?
Helps loosen the chromatin out and helps get replication started
What is a retinoblastoma?
(2)
The retinoblastoma protein is a tumor suppressor protein that is dysfunctional in several major cancers.
One function of pRb is to prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide.
Write a note on cyclin E
(4)
Binds to CDK2 in the G1 phase
Required for the transition from G1 to S phase
Cyclin E/CDK2 complex phosphorylates p27Kip1 (an inhibitor of cyclin D)
Phosphorylation of p27Kip1 tags it for degradation, promoting expression of cyclin A, allowing progression to S phase
What does cyclin E bind to and when?
Binds to CDK2 in the G1 phase
Required for the transition from G1 to S phase
What does Cyclin E/CDK2 complex?
Phosphorylates p27Kip1
What is p26Kip1?
An inhibitor of cyclin D
What happens when p26Kip1 is phosphorylated?
(2)
It is tagged for degradation
This promotes the expression of cyclin A which allows progression to S phase
Write a note on cyclin A
It can activate two different CDKs, CDK2 or CDK1
It functions in both S-phase and mitosis
Helps trigger the G2/M transition
Levels increase with the onset of the S phase and contribute to the stimulation of DNA synthesis
In early mitosis it drives the initiation of chromosome condensation
Write a note on cyclin A
(6)
It can activate two different CDKs, CDK2 or CDK1
It functions in both S-phase and mitosis
Helps trigger the G2/M transition
Levels increase with the onset of the S phase and contribute to the stimulation of DNA synthesis
In early mitosis it drives the initiation of chromosome condensation and nuclear envelope breakdown
CDK-cylin A activity peaks at G2/M
Inactivation of cyclin A arrests the cell cycle in G2
When does Cyclin A function
It functions in both S-phase and mitosis
What CDKs does cyclin A work with?
CDK2 or CDK1
What does cyclin A trigger?
G2/M transition
What does the cyclin A peak do?
Contribute to the stimulation of DNA synthesis
What does cyclin A do in mitosis?
In early mitosis it drives the initiation of chromosome condensation and nuclear envelope breakdown
What does cyclin A inactivation do?
Inactivation of cyclin A arrests the cell cycle in G2
Write a note on cyclin B
(4)
A mitotic cyclin
Binds to CDK1
Activity of cyclin B/CDK1 complex rises through the cell cycle until mitosis then it falls abruptly due to degradation
The complex is called promoting factor or mitosis promoting factor (MPF)
What phase does cyclin B work in?
Mitosis
Describe the activity of cyclin B
Activity of cyclin B/CDK1 complex rises through the cell cycle until mitosis then it falls abruptly due to degradation
What does cyclin B bind to?
CDK1
What is cyclin B/CDK 1 complex also called?
Maturation Promoting Factor
Mitosis Promoting Factor
Write a note on Mitosis Promoting Factor
(2)
In the 1970s cells in M phase contained an unknown factor that could force frog egg cells stuck in G2 phase to enter M phase
MPF was identified in 1980s to be a CDK bound to its M cyclin partner
What is the APC complex?
The anaphase-promoting complex/cyclosome
What does Mitosis promoting factor trigger?
The anaphase-promoting complex (APC)
Write a note on the APC
(3)
A protein complex that causes M cyclins to be destroyed starting in anaphase
When M cyclins are destroyed it pushes the cell out of mitosis, allowing the new daughter cell to enter G1
The complex also causes the destruction of the proteins that hold the sister chromatids together, allowing them to separate in anaphase
