Cell Cycle Regulation Flashcards
Each cell cycle is coordinated with the timing of (3)
1) DNA replication
2) Cell Division
3) Growth
What controls cell progression cycle?
Regulatory proteins
If the coordination of cell cycle phases FAILS…
Daughter cells may contain an incomplete copy of the genome or be too small (leading to cell death)
The Cell Cycle
1) G1 Phase
2) S Phase
3) G2 Phase
4) M Phase
G1 Phase
AKA “Gap 1” or Growth 1
–> Cell growth occurs and cell prepares for DNA replication
S Phase
AKA Synthesis Phase
–> Synthesis (replication) of DNA occurs
G2 Phase
AKA “Gap 2” or Growth 2
–> Cell growth occurs and cell prepares for chromosomal segregation
M Phase
AKA Mitotic Phase
–> Mitosis occurs followed by cytokinesis
G0 Phase
“Quiescent/Quiet” Phase
–> A non-dividing state: An exit from the cell cycle
Most human cells are in what phase?
G0
LOOK AT GRAPHS with the 2 lines showing total cell mass and DNA content over a cell cycle
How long does it take one cell to go through one cell cycle?
It depends on the cell type
Cells that divide frequently
Skin Cells
Cells that have the ability to divide but only do so when they must
Liver Cells
Cells that rarely/never divide past maturity
Nerve and muscle cells
Cells that stop and start dividing based on conditions
Cells involved in wound repair
What was the main research question regarding the cell cycle control system?
What tells a cell whether to progress through the cell cycle or stop?
Determining the cell cycle control system STUDY:
2 hypotheses
1) Each cell cycle EVENT triggers the next event
2) Each event in the cell cycle is driven by specific molecules present in the cell
Determining the cell cycle control system STUDY:
Experiment Design + Results
Experiment #1
–> Fused G1 cell with S cell === G1 cell entered S-phase!
Experiment #2
–> Fused G1 cell with M cell
=== G1 cell entered M-Phase (without going through S-phase first; immediately began dividing)
Determining the cell cycle control system STUDY:
Main findings + Conclusion
Fusing a G1 cell with a cell in M or S phase caused the G1 cell to initiate cell division or DNA replication
Conclusion = Diffusable molecules trigger a cell to enter a later phase of the cell cycle (induces different phases)
Cell Cycle Control System
A cyclically operating set of molecules in the cell that both triggers and coordinates key events in the cell cycle
The cell cycle control system relies on…
Internal and External signals for regulation of the cycle at checkpoints
The cell cycle control system has two types of mechanisms:
1) Mechanisms that REPRESS cell cycle progression
2) Mechanisms that INDUCE cell cycle progression
Checkpoints
“Molecular brakes” –> Can halt the cell cycle
–> A control point where stop and go-ahead signals can regulate the cycle
Signals registered at the checkpoints indicate…
if key processes have been completed SUCCESSFULLY
and therefore, whether or not it is safe to move forward
The major checkpoints
1) G1 checkpoint
2) G2 checkpoint
3) M checkpoint
G1 Checkpoint
AKA START or Restriction Point (The most important checkpoint)
–> Checkpoint that halts or allows for progression into the S phase
–> Cell decides whether to continue on to division, delay division, or enter G0 state
G1 Checkpoint checks for (4):
Checks for FAVORABLE CONDITIONS
1) Cell size
2) Nutrient/Energy (does cell have what it needs to divide?)
3) Growth Factors (Molecular signals)
4) DNA integrity
If the cell receives a GO-AHEAD signal at G1 checkpoint…
The cell WILL DIVIDE: It has committed to dividing
–> No matter whether it gets delayed in subsequent or whether it is successful or not, the cell will progress to division
–> Only way out: APOPTOSIS
If the cell does NOT receive a GO-AHEAD signal at G1 checkpoint…
The cell will enter the G0 state (exits the cell cycle)
G2 Checkpoint
“DNA Damage” or “ENTER M-Phase” Checkpoint
–> The point between G2 and M phase: Can delay the progression into mitosis if needed (if DNA errors are found)
G2 Checkpoint Checks for (2):
Any issues with the DNA:
1) DNA Damage
2) DNA replication completeness
The G2 checkpoint will HALT the cell cycle if…
DNA damage is found
–> Will not proceed until repairs are made
The G2 checkpoint will progress the cell cycle if…
No errors in the DNA are found
–> Pushing the cell into the M-Phase
If DNA errors are irreparable, what occurs at the G2 checkpoint?
The cell may induce apoptosis
The “question” G2 checkpoint asks the cell
Are you ready for mitosis?
The “question” G1 checkpoint asks the cell
Are conditions favorable and appropriate to begin cell division process?
M Checkpoint
“Metaphase” or “Mitotic Spindle” Checkpoint
–> Checkpoint occurs between metaphase and anaphase
–> Will delay anaphase until all necessary conditions are met
M Checkpoint checks for:
1) Proper attachment of sister chromatids to the microtubules from the mitotic spindle at the metaphase plate
Mitosis is paused at the M Checkpoint if…
Any chromosomes are found to be improperly attached to or not attached at all to the microtubules
Anaphase begins at the M checkpoint if…
All chromosomes are properly attached to the mitotic spindle
= Activation of APC
Importance of M Checkpoint
Ensures that daughter cells do not end up with missing or extra chromosomes
(ensures proper chromosomal segregation)
An additional checkpoint we know of…
Intra-S Phase Checkpoint
If the G1 checkpoint is passed prematurely…
= Insufficient cell size
–> Daughter cells will be too small to support life
If the G2 checkpoint is passed prematurely…
= Incomplete chromosome replication
–> Daughter cells will lose genetic info
It the M checkpoint is passed prematurely…
= Incomplete attachment of chromosomes to microtubules
–> Daughter cells will receive wrong # of chromosomes
Cancer cells grow out of control because… (2)
1) Don’t respond to normal signals that regulate the cell cycle
2) Lost the ability to survey whether condition of okay or not
Rhythmic fluctuations in the _______ and _______ of cell cycle control molecules pace the ________________________________
1) Abundance
2) Activity
3) sequential events of the cell cycle
Regulatory Molecules of the Cell Cycle
1) Protein Kinases (cyclin dependent kinases)
2) Cyclin
Protein Kinases
Enzymes that catalyze the addition of a phosphate group to a target protein (phosphorylates)
–> Convert ATP to ADP and uses the free Pi group to attach to the target protein
Impact of Phosphorylation on Proteins
Phosphate is a very negatively charged group which can dramatically change the shape of a protein and therefore, the function of the target protein
What molecule is the opposite of a kinase?
PHOSPHATASE
–> Dephosphorylates
Kinases that drive the cell cycle
Cyclin Dependent Kindases (cdks)
Cyclin Dependent Kinases (cdks)
Kinases that rely on cyclin to activate
Cdks are usually ________________ in the cell
INACTIVE
–> They must bind to cyclin to activate
The concentration of cdks …
Remains constant (ALWAYS present in cells)
Cyclin
A protein that gets its name from its cyclically fluctuating concentration in cells
(Binds to cdks to activate them)
The activity of a cdk rises and falls with…
changes in the concentration of its cyclin partner
Cyclin concentration is…
Always changing
–> Cyclin is only made at certain times in the cell cycle
Upon binding of cyclin and a cdk, what occurs to the cdk?
The active site is exposed, allowing the target protein to bind and phosphorylation to occur
G2 Checkpoint cdk complex:
MPF = “Maturation (Mitosis) Promoting Factor”
MPF
“Maturation (Mitosis) Promoting Factor”
What was the first cyclin-cdk complex discovered?
MPF
G2 Checkpoint cdk complex:
As cyclin conc. peaks…
MPF activity peaks
G2 Checkpoint cdk complex:
Synthesis of cyclin begins when? Why?
In LATE S-PHASE –> Synthesis continues through G2
= cyclin accumulation
–> Cannot be made in G1 or M phase as cyclin degradation occurs in these 2 phases
How is MPF produced?
Cyclin binds to cdk forming the MPF complex
When enough MPF molecules accumulate…
The cell passes G2 checkpoint and enters mitosis
How does MPF promote mitosis?
By phosphorylating various proteins
What proteins does MPF phosphorylate?
(What is the result of this?)
1) Chromosomal proteins –> Initiates chromosomal condensing (In prophase)
2) Microtubule associated proteins –> Activates mitotic spindle
(In prophase)
3) NUCLEAR LAMINS –> Causes disassembly of the nuclear membrane (In Pro-Metaphase)
What does MPF do during anaphase?
MPF phosphorylates an enzyme that degrades the cyclin component of MPF
–> Causes its own destruction
G2 Checkpoint cdk complex:
What is the result of cyclin destruction?
MPF deforms which causes M phase to terminate and cell to enter G1 phase
What happens to MPF complex in G1?
1) Cyclin degradation continues
2) MPF cdk gets recycled for the next cell cycle
Internal Signals for Cell Cycle Control
Report whether crucial cellular processes that should have been completed have in fact been completed correctly
(Determining cell cycle progression)
External Signals for Cell Cycle Control
Signals from outside the cell are transmitted within the cell by signal transduction pathways
(Usually have to do with G1 checkpoint –> deciding whether to begin cell division or not)
Signal for the M Checkpoint
APC
Does the M Checkpoint involve external or internal signalling?
Internal Signal (APC)
What activates APC?
A tension-dependent kinase
Once APC is activated…
it enables SEPARASE to cleave the cohesins between sister chromatids (allowing for anaphase to occur)
Wound healing external signalling
When an injury occurs, platelets in the area release PDGF, a growth factor that binds to cells with the specific receptor
PDGF
Platelet-Derived Growth Factor
–> The binding of PDGF to receptors (TK) on the outside of other cells = signal transduction pathway which causes cells to pass the G1 checkpoint and begin division
What receptor does PDGF bind to?
Tyrosine-Kinase Receptor
Transduction pathway due to PDGF result in…
An increase in G1 cyclin
Process of PDGF Signaling
1) PDGF arrives from other cells
2) PDGF binds to TK receptor = triggers cascade
3) Increase in G1 cyclin
4) Cyclins activate cdks
5) Cdks activate many S PHASE PROTEINS (by phosphorylation)
6) Activated S-Phase proteins push cells to division (pass G1 checkpoint)
Growth Factor
A protein released by certain cells that stimulate other cells to divide
EXTERNAL signals that STIMULATE cell division
What are the scientific applications of growth factors?
Scientists use growth factors to proliferate cell cultures needed to conduct their studies and experiments
Muscle Growth Cell Signaling
Muscle cells DO NOT usually divide due to the presence of a growth inhibitor (myostatin)
Myostatin
A protein that inhibits the growth (division) of myoblasts (fuse with each other to form skeletal muscle cells)
What does myostatin do? What is its effect?
Acts by CONTINUOUSLY inhibiting the growth of muscles beginning early in embryonic development and continuing through life
–> Works to prevent crazy muscle growth
How does myostatin work?
Myostating induces the degradation of G1 cyclin –> Causing a blockage in the passage of the cell from G1 to S phase
–> ARRESTS the cell in G1
MSTN
Myostatin gene
What occurs when myostatin is mutated?
Can cause excessive growth of muscles in organisms
–> Inhibiting myostatin removes the inhibition of cell division in muscle cells
Examples of Myostatin Mutation (2):
1) The bully whippet (dog)
2) Belgium blue breed (cattle)
What are the implications of inhibiting myostatin?
1) Livestock
2) Human Health
3) Athletics
How are Myostatin and PDGF OPPOSITES?
PDGF = Activates production of G1 cyclin
Myostatin = Triggers degradation of G1 cyclin
