Lecture 18 -cell Cycle Flashcards
What is a cell cycle
A series of events that need to tAke place for the cell to divide and its content to duplicate
How many phases are in the eukaryotic cell?
4
What are the phases of cell didvisionnin euk cells?
G1
S -DNA replicates
G2
M- mitosis + cytokinesis
Which phase takes the longest and how much
Interphase take 90% of time
Cells that are stuck at the end of G1 phase are called…
Cells in G0 state ( arrest stage)
Quiescent
What are the 3 cell cycle groups
1- cells that enter a permanent G1 phase (Arrest stage )
Once differentiated Remain in this stage untill they die
2- cells that don’t divide normally but can be induced
3- cells that divide regularly
Most cells fall in which type of category?
Mostly cells are in G0 state but most of them can re enter the cell cycle when it needs to divide
What determines how much time the whole cell cycle will take
The amt of time taken by the interphase
Whats the main thing happening in G1 phase?
Cell grows and carries out normal metabolism
Organelles duplicate
S ( synthesis)
DNA and chromosome duplication
What happens in G2 phase?
Cell grows and prepares for mitosis
What happens in M phase?
Mitosis/ karyokinesis
Cytokines
What is required to move on to the next stage
Cell signalling
What signals the cells in Go to divide , what initiates the cell cycle?
Ras signalling of MAP kinase cascade triggered by RTK receptor
How does the RTK triggers or speeds cell division
1- MAP kinase cascade triggered by RTK
2- cells produce Epidermal growth factor
2- this trigger stem cells and other cells
4- this signalling pathway turn on the transcription of specific genes , Eg cyclins , this speeds up cell division
Cell cycle control system is similar in euk
True
CELL CYCLE CONTROL SYSTEM
————- is like the black box in the cell
Cell cycle control.
What are the major components of the cell cycle control system?
1- cyclins
2- cyclin dependent protein kinases ( cdks)
How does the cell cycle control system work ?
The cell control cycle has brakes or checkpoint to arrest the cell cycle
If a stage is incomplete, the process will come to a stop
Eg- if DNA is damaged , the cell cycle comes to a stop, the DNA is repaired before proceeding
Overall Purpose of the cell cycle control system ?
Ensures that the key processes in the cycle occur in the proper sequence
Maturation promoting factor is a complex of
Cdk 1 + cyclin B
Role of cyclin in maturation promoting factor- MPF /M cdk ( cyclin B + cdk)
- regulates cdk activity
- levels rise and falls throughout
- helps direct the cdk to the target proteins that the cdk phosphorylates
Role of cdk in maturation promoting factor
- a kinase protein that adds a phosphate from ATP to other proteins , to modify target protein
How does Progress to the M phase occur?
-Cdk+ cyclin = enzymatically active (M cdk)
-cdk is phosphorylated at 2 adj sites by inhibitory kinase wee1
-wee1 keeps it inactive until cdc25 phosphatase removes the phosphate
The complex the:-
- The cyclin also helps direct the cdk to the target proteins that the cdk phosphorylates
- cyclin helps cdk enzymic activity
Level of cyclin during and btw stages
Entering mitosis - increasing towards the highest point
Mitosis- highest point
Leaving mitosis- steep fall and 0 before leaving
Entering interphase - 0
Interphase - 0 right in beg , then gradually increasing
Leaving interphase - gradually to increase
What regulates the activity of cdks
Accumulation of cyclin
Formation of cyclin - cdk complex drives entry to what stages
S phase and M phase
What helps in the formation of active M cyclin - cdk complexes
Increasing concentration of relevant cyclin called - M cyclin ( cyclin B)
What happens when enough MPF is triggered ?
It triggers mitosis
- prepares chromosome for degradation by phosphorylates H1 histones - causes DNA to condense
- activates micro tubules proteins to assemble the mitotic spindles
- shutdown Wee1 and promote production of mcdk - when an mcdk is activated it phosphorylates more cdc25 which then removes phosphate from mcdk , activating it
POSITIVE FEEDBACK LOOP
Overall what determines if the cell cycle will transition from one phase to another
Cyclin / cyclin Cdk complex
Eg Mcdk
G1/ Scdk
Scdk
What drives entry to S phase through G1 phase
Active G1/S cdk phosphorylates regulatory proteins that activate transcription of genes required for DNA replication
What drives entry to M phase
When the M cdk complex is active , the cdk can phosphorylate a different set of regulatory proteins
How is cyclin concentration regulated?
Hint- how is the amount of any protein regulated
Regulated by ubiquitin medated degradation
Uniquitin tags S or M cyclin for degradation in proteosome
As said earlier whta regulates cdk activity
Cyclin
Eg cyclin degradation inactivates cdk
What regulates cyclin - cdk
Kinases and phosphatase regulate activation and inactivation
And cyclin regulates formation
How is M cdk activated?
- once the M cyclin cdk is active
- it is phosphorylated at 2 adj sites by an inhibitory protein kinase called wee1
- this this keeos the M cyclin cdk inactive untill
- phosphatase Cdc25 removes these phosphates
Wee 1 is part of checkpoint , what does it check ?
Checks if cell is big enough for mitosis
Activity of cdk can be blocked by 2 methods , state them ?
- phosphorylation by inhibitory kinase wee1( discussed earlier)
- also be blocked by cdk inhibitors (p27)
How do cdk inhibit cdk activity⁉️⁉️
- Cdk inhibitory protein (p27) binds to an active cyclin cdk complex
- attachment prevents the cdk from phosphorylating target proteins required for progress through G1 inti S phase
Jist like wee1, cdk inhibitors are also part of checkPoint . What do they check
Check if envr conditions are favourable
Also gives more time for cells to grow
What happens DNA replication not complete or DNA damage during S or G2 phase
cdc25 removed phosphate from M cdk ( activating it) ,allowing it to progress through mitosis. When DNA is damaged , Inhibition of activating phosphatase Cdc25 , Blocks entry to mitosis- part of G2 checkpoint
What happens if Chromosomes not attached to spindles
Inhibition of APC/C activation delays exit from mitosis
What happens if Environment not favourable in
G1
G2
Cdk inhitors (p21) inhibit S- cdk , block entry to S phase Cdc25 inhibited, preventing activation of mcdk
What promotes the production of cyclin that stimulate cell division
Mitogens
Mitogens turn on cyclin genes by activating cell signalling pathways
Absence of mitogens causes the cell to arrest in G1 or G0
What promotes cell proliferation and how ?
Mitogens , by inhibiting the Rb protein
- In the absence of mitogens, de phosphorylated RB proteins holds specific transcription regulators in an inactive state
- Mitogens binds to the cell surface receptors activate intracellular signalling pathways that lead to the formation and activation of G1- cdk and G1/ s - cdk complexes
- these complexes phosphorylate and thereby inactivate , the Rb protein , releasing the transcription regulators needed to activate the transcription of genes / cyclins required for entry in S phase
Which transition itself is a critical checkpoint
G1 -> S phase
What is like a 4 way stop ?
G1 to s phase
What are the things that can happen in the g1 to s transition
1- cell can commit to completing another cycle
2- cells can withdraw temporarily until conditions are right
3- withdraw from cell cycle and enter g0 , either temp or permanently in case of terminally differentiated cells
Then what exactly decides what to do out of these 3
Intracellular and extracellular signals decide if the cell proceeds to S phase or G0 phase
We saw that s cdk and m cdk is 0 at G1 phase , how does this happen
S cdk and M cdk are inactive in G1
- by eliminating all existing cyclins
- block the synthesis of new cyclins
- recruit cdk inhibitor proteins
What happens if DNA is damaged in G1
DNA damage can arrest cell cycle in late G1 ( G0 arrest phase)
- kinase work by
activating Tp53 and
haling its rapid degradation - activated p53 accumulates and stimulates the transcription of the gene that encodes the cdk inhibitor protein p21
P21 binds to G1/ S- cdk and S-cdk and inactivates them , so the cell cycle arrests in G1
3 ways cell enter non dividing stages
1- cells can delay progression through cell cycle until conditions become favourable or until DNA damage is fixed
2- cells can also withdraw from cell cycle permanently ( terminally differentiated cells)
- cyclin and cdk genes permanently shut down
- eg muscle cells, nerve cells
3- cells can withdraw from cell cycles temporarily
- enter into G0 until stimulated to proliferate
Cell division rate depends on
The time soent in g0 and G 1 phase
Role of S cdk in S phase
- initiates DNA replication and blocks re replication
Activates helicase and recruits other proteins like (Cdc6) to the replication fork
Cyclin concentration is regulated by
Ubiquity medial degradation
Or
Transcription genes activated by mitogens or RAS signalling
