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Eukaryotic Cell cycle
Terms in this set (101)
Cellular replication produces what?
Produces two daughter cells that are identical to the parent cell (the genome is identical to parent cell)
Cellular respiration results in two daughter cells that are identical to the parent cell. To get the same genome in the daughter cells as the parent cells, what is required in cellular respiration?
1. Accurate duplication of chromosomes
2. Precise segregation of chromosomes
Improper segregation of chromosomes during cellular replication causes what?
Aneuploidy - an abnormal number of chromosomes
Aneuploidy can cause either an ______ or _____ representation of genes that can be either lethal or causes disease (ex: _______)
Over-representation (greater than 2 for somatic cell)
Under-representation (less than 2 for somatic cell)
Cancer *the cancer cell karyotype on the slide showed multiple aneuploidy with some under-represented chromosomes such as once copy and over-represented such as four copies
What is the order of the phases in the cel1 cycle?
How many period of growth are there in the cell cycle?
Two period of growth - G1 and G2 aka Gap1 and Gap2
In what phase of the cell cycle does the replication of the DNA occur?
Synthesis or S phase
In what phase of the cell cycle does segregation of the chromosomes occur?
Mitosis or M phase
Cell division occurs during what phase of the cell cycle?
Cytokinesis (at the end of the mitosis phase)
The _______ growth phase is involved in growth and normal metabolic roles
The ______ growth phase is involved in growth and preparation for mitosis
G2 *note that G2 comes after DNA replication
What is interphase of the cell cycle?
G1, S, and G2 make up interphase
_______ is the intervals between M phases
T or F: the time it takes to complete the cell cycle is constant across all cells
False: the time varies. Most mammalian cells complete the cell cycle in about 24 hours, yeast take about 90 minutes, some cells don't divide regularly
Most mammalian cells complete the cell cycle in about _______ hours.
_______cells are the differentiated cells that perform the various function of the organelles that are not dividing much, if at all. (These cells do not divide regularly)
Post-mitotic *may be calmed something else
Before a cell can divide it must _____. This is accomplished in which phases of the cell cycle.
Grow - G1 and G2
The cell is metabolically active in the ____phase.
Which phase comprises the largest segment of the cell cycle with regards to time?
The G1 phase takes approximately 11 hours (for a 24 hour cycle)
What are some exceptions to the normal progression of the cell cycle?
Early cell divisions of embryos proceed without a G1 or G2 phase
What is the consequence of the early cell divisions of embryos not containing a G1 or G2 phase?
Cells become progressively smaller
What is the cell cycle for cells in the early embryo?
They consist of an S phase followed by an M phase, with no growth phases, which results in a decrease in the daughter cell size with each cell division. One large cells is divided into smaller and smaller cells
What allows for the early embryonic cells to not have growth phases in their cell cycle?
The RNA and protein that are placed into the oocyte prior to fertilization are used in the first few divisions after fertilization, which allows for the growth phases to be skipped
The S phase consists of DNA replication and takes approximately ______ hours
For faithful transmission of the genome to the daughter cells, DNA replicates how many times during a cell cycle?
ONLY ONE TIME
What ensures that the DNA is replicated ONLY ONE TIME during the cell cycle (specifically during S phase)? What is this process regulated by?
1. Binding of MCM (minichromosome maintenance) helicase to replication origins during late G1, prepares the ORC for initiation replication
2. Kinase activity during late G1/S prevents reinitiation of replication
(The origin of replication complex binds to the DNA and primes the DNA for replication. The MCM binds to the origin during late G1 which prepares the ORC for replication. Kinase activity during late G1/S activates the MCM by phosphorylation which leads to the helicase activity that begins process of replication. The phosphorylated MCM is no longer able to bind to the origin complex and is targeted for degradation. So the process of replication cannot begin again until more MCM is synthesized in the G1 phase and activated by kinase activity in the late G1/S phase. Ensuring only one round of replication per cell cycle)
The G2 phase is the second growth phrase that prepares the cell for ________ by synthesizing the proteins needed for this process?
The G2 phase takes approximately _______ hours.
Four (much shorter phase in comparison to G1 and S)
List the time period that each phase of the cell cycle takes in order of progression through the cell cycle
1. G1 = 11 hours
2. S = 8 hours
3. G2 = 4 hours
4. M = 1 hour
The segregation of chromosomes into two daughter cells occurs during ____ phase
The M phase ends with what?
Cytokinesis - separation of the two daughter cells
The M phase is further divided into what phases associated with specific events necessary to segregate the chromosomes?
*sometimes prometaphase placed here
(Followed by cytokinesis)
Which is the shortest of the cell cycle phases?
The M phase takes approximately one hour
The cell cycle is regulated by both external signals and internal regulators. List the molecules that belong in each of these categories.
External signals - Growth factor
Internal regulators - signaling cascades, cycling, cyclin dependent kinases (Cdk), Cdk inhibitors, checkpoints
The external signals such as ________ link cell division (and thus progression through the cell cycle) to conditions in the cell's environment.
The signaling cascades that act as internal regulators of the cell cycles are downstream mediators of ______. _______
______ regulate the activity of cyclin dependent kinases
The __________ activate components of pathways responsible for DNA synthesis and events of mitosis
Cyclin dependent kinases (Cdk)
Cdk inhibitors provide an additional control of the cell cycle in specific situation such as what?
1. Absence of growth signals
2. Presence of DNA damage
_______ are quality control check that prevent progression through cell cycle in the presence of errors
Checkpoints (ensure that mutations are not passed on to daughter cells)
At what point does a cell commit to the cells cycle progression?
When it passes the restriction point (R) late in G1 phase *animal cells
Entry into the cell cycle is controlled by availability of ______ _______
In the absence of growth factors, what happens to a cell with regards to the cell cycle?
The cell enters a quiescent state called G0 (because it cannot pass the restriction point in late G1 in the absence of growth factors)
What can move a cell out of the G0 phase?
When stimulated by growth factors, cells enter the cell cycle in G1
________ signaling links progression through the cell cycle to conditions in the cell's environment
Growth factor binding to its receptor initiates a signaling cascade leading to the synthesis of what?
Cyclin D (side note: frequently uses Ras pathway for this)
If growth factors are withdrawn before cell passes R, what happens?
The cyclin D will be degraded and the cell will enter G0 (until growth factors are reintroduced into the cell's environment)
T or F: If the cell is already past R (the restriction point), when growth factor is withdrawn, the cell will enter G0
FALSE! If the cell is already past R, when growth factors are withdrawn, the cell cycle will be completed (so movement past the restriction point is a commitment to complete that cell division)
How do growth factors help to drive the cell past the restriction point to commit to the cell cycle?
Growth factors bind to receptors which leads to the synthesis of D-type cyclins through Ras/Raf/MEK/ERK signaling pathways. The D-type cyclins bind to Cdk4,6 which activates it. The activity of the cyclin dependent kinase helps to drive the cell through the restriction point
Cyclins bind to ________, to regulate their activity.
Cyclin dependent kinases (Cdk)
T or F: The cyclin levels remain constant throughout the cell cycle
False: the cyclin levels fluctuate during the cell cycle (they will get slow increase and then sudden decreases in levels, cyclin B levels drop at the end of mitosis??)
What are the Cdks involved in regulation of the cell cycle?
What are the cyclins that are involved in regulation of the cell cycle?
Cyclins A, B, D or E
What is the function of Cdk and what is the function of cyclin?
Cdk phosphorylate specific substrates after pairing with specific cyclin in different phases of the cell cycle
Cyclins controls the activity of the Cdks through pairing with specific Cdk in different phases of the cell cycle
List the Cdk and cyclin for each of these phases of the cell cycle
1. Early G1 through R
2. G1 to S transition
3.. S phase
4. S to G2 transition
5. G2 to M transition
1. Early G1 through R - Cdk 4,6 and cyclin D
2. G1 to S transition - Cdk2 and cyclin E
3.. S phase - Cdk2 and Cyclin A
4. S to G2 transition - Cdk1 and Cyclin A
5. G2 to M transition - Cdk1 and Cyclin B ***
(Maybe practice drawing out cell cycle and where each of these falls)
The mitosis or maturation promoting factor (MPF) is a prototype of cyclin/Cdk complexes. What is it made up of?
Cdk1 and Cyclin B
*side note: Cdk1 was the first cyclin dependent kinase discovered and is sometimes called by its original name - cdc2
What does MPF regulate?
Regulates the transition from the G2 phase to M phase (remeber, that MPF is composed of Cdk1 and cyclin B)
How is Cdk1 activation primed? What are the three components of priming effect of Cdk1?
1. Binding of cyclin B
2. Phosphorylation at Thr 161 - activating
3. Phosphorylation at Tyr 15 (or Thr 14 depending on the particular Cdk1) -inhibitory
These amino acids are sites on the Cdk1 that are phosphorylated. One is activating, the other is inactivating so activation of Cdk1 would require the removal of the inactivating phosphoryl group
How is the Cdk1 activated?
Dephosphorylation of Cdk1 by Cdc25 phosphatase that removes the inhibitory phosphates at Tyr 15
(The Cdk1 also requires the activating phosphorylation and the binding of cyclin B to be active, these are present prior to this step in the process of priming the Cdk1)
Cdk1 is a kinase that phosphorylate proteins that control _______when in its active state.
How is the Cdk1 inactivated?
1. Degradation of cyclin B
2. Dephosphorylation of Cdk1 (at the Thr 161 site with the activating phsophoryl group)
What triggers the exit form mitosis?
The degradation of cyclin B. (So cyclin B levels fluctuate in the cell, they slowly increase throughout the cell cycle and then suddenly drop near the end of M phase)
List the cycle of Cdk1 activation/inactivation beginning with the first thing to occur in the cell cycle
1. Synthesis of new Cyclin B and decreased degradation of cyclin B causes increase of cyclinB/Cdk1 complex
2. Phosphorylation of cyclinB/Cdk1 complex
A. Wee1 kinase adds inhibitory phosphate at Try 15
B. CDK activating kinase (CAK) adds activating phosphate to Thr 161
3. Cdc25 phosphatase removes inhibitory phosphates (the Cdk1 is active at this point)
4. Active CyclinB/Cdk1 acts as a kinase phosphorylating its targets
5. APC/Cdh1 ubiquitnates and targets the cyclin B for proteasome (*Cdk1 is inactive at this point because requires binding to cyclin B to be active)
6. Dephosphorylation of the Thr 161 inactivates the Cdk1
What adds the activating phosphorylation to Thr 161 in Cdk1?
Cdk activating kinase (CAK)
What adds the inhibitory phosphate at Tyr 15 in Cdk1?
What ubiquitinates the cyclin B? Which has what effect?
targets it for degradation in the proteasome
What are four things that act as regulator of Cdks?
1. Association of Cdks with cyclins (dependent on cyclin synthesis and degradation)
2. Phosphorylation of Cdk - ex: Thr 161 by CAK
3. Dephosphorylation -ex: removal of inhibitory phosphorylation Tyr 15 and thr14 by Cdc25 phosphatase
4. Association with Cdk inhibitors
Which family of Cdk inhibitors inhibits progression through G1 and which Cdk do they inhibit to perform this function?
Ink 4 family
Binds to Cdk 4,6 and inhibits progression through G1
What are the members of the Ink 4 family of Cdk inhibitors? (Prevent progression through G1)
p15, p16, p18, p19
Which family of Cdk inhibitors (CKI) inhibits progress through G1 and S? What do they bind to, to perform this function?
Binds to Cdk2/Cyclin A or E and inhibits progress through G1 and S
What are the members of the Cip/Kip family of Cdk inhibitors that inhibit progress through G1 and S?
P21, p27, p57
What is a gene that is mutated in a tumor of the eye?
What is the function of the retinoblastoma protein produced from the retinoblastoma gene?
It is a key regulator of transcription of genes required for cell cycle progression and DNA synthesis (ex: Cyclin E-involved in transition through restriction point and into S)
What happens in the under-phosphorylated form of Rb?
It binds E2F and represses transcription
*E2F is a transcription factor that is inactive when bound to E2F
Rb is phosphorylated by what protein and what effect does this have?
Cdk4,6/CyclinD complex phosphorylates Rb which dissociates from E2F and transcription is activated
*the E2F transcription factor is active when not bound by Rb so it can initiation transcription of cyclin E and other proteins that are needed for progression through the cell cycle and DNA synthesis
What are the targets of Cdk4,6/cyclin D (present in the G1 through R portion of the cell cycle)
Retinoblastoma protein (Rb) which when phosphorylated dissociates from the E2F and results in activation of transcription
Passage through R and initiation of DNA synthesis requires activation of _________
Before R (early G1), Cdk2/cyclin E is inhibited by ______
(A Cdk inhibitor of the Cip/Kip family)
How does the Cdk2/Cyclin E complex become activated as the cell progresses through the G1 phase of the cell cycle (activation of this complex enables the cell to pass the restriction point.)
1. more cyclone E is synthesized
(as a result of active Cdk 4,6/cylinD phosphorylation Rb) *we can see now how the removal of growth. Factors causing the degradation of cyclin D prevents the movement of the cell through the restriction
2. And repression by p27 is relieved
What are the ways in which the repression of Cdk2/cyclin E by p27 is relieved as the cell progresses through G1 allowing for activation of this complex?
1. p27 binds Cdk4,6/cyclin D (which makes sense because this complex will need to be inhibited to move to the next phase)
2. p27 also targeted for degradation
3. AND p27 synthesis is decreased
*made a point of mentioning the last point so it may be a test question
Once Cdk2/Cyclin E is activated, DNA replication is initiated as a result of what?
The Cdk2/Cyclin E phosphorylated the MCM helicase which initiates the process of DNA replication
*note: during S, Cdk2 prevents reassociation of MCM with ORC ensuring DNA is only replicated once
***look at the summary chart for the regulation of the cell cycle to organize all this info into one complete picture connecting the dots between growth factor effect and the transition into DNA synthesis
________ in each phase coordinate events to ensure that the next phase does not begin before that phase is completed.
The checkpoints activate a signal pathway that leads to cell cycle _______ until the problem can be corrected. What happens if the problem cannot be corrected?
If it can't be corrected, cell death is induced
________ protect the cell from replication errors or passing down damaged DNA.
DNA damage checkpoints
________ ensures chromosomes are aligned properly so each daughter cell receives one copy of each chromosome
Spindle Assembly Checkpoint
Where are the DNA damage checkpoints located?
In late G1 phase, S phase, and late G2 phase
Where is the spindle assembly checkpoint located?
How many checkpoints are there in the cell cycle and where are they?
3 DNA damage checkpoints - G1, S, G2
Spindle assembly checkpoint -M phase
The ______ ensures that the cell does not proceed to S phase (DNA replication) with damaged DNA
G1 phase DNA damage checkpoint
The _____ continuously monitors for errors in replication and DNA damage.
S phase DNA damage checkpoint
The ______ is the final monitor for DNA damage before segregation of the chromosomes in M phase
G2 phase DNA damage checkpoint
The _______ checkpoint monitors alignment of chromosomes on the metaphase plate during M phase
_____ and _____ are kinases that are part of damage recognition complexes in the DNA damage checkpoints
ATM and ATR
How does DNA damage lead to arrest of the cell cycle?
A. Double stranded break is detected by ATM which phosphorylates ChK2 activating it. The ChK2 phosphorylates and inhibits Cdc25
B. Single-stranded or unreplicated DNA is recognized by ATR which then phosphorylates ChK1 activating it. The ChK1 phosphorylates and inhibits Cdc25 phosphatase
2. Phsophrylated Cdc25 is inhibited from performing its function so the inactivating phosphate groups cannot be removed from Cdk1 or Cdk2 depending on the part of the cycle the cell is in
A inhibition of Cdk1 leads to G2 arrest
B Inhibition of Cdk2 leads to G1 and S phase arrest
WOULD BE BETTER TO LOOK AT DIAGRAM FOR THIS BECAUSE TWO PATHWAYS CONVERGE AND THEN DIVERGE AGIAN
ATM and ATP recognize DNA damage and phosphorylate downstream kinases ______ and ______, which then phosphorylate _______, which prevents activation of ______ and ______
ATM and ATR phosphorylate ChK1 and ChK2 which is each capable of phosphorylating Cdc25 phosphatase which prevents activation of Cdk1 and Cdk2 by preventing the removal of the inactivating phosphate group
The ______ kinase in DNA damage checkpoint recognizes double-stranded breaks while the ______ recognizes single-stranded or unreplicated DNA
ATM -double-stranded breaks
ATR - single-stranded or unreplicated DNA
Which DNA damage checkpoint proteins also phosphorylate p53?
ATM and ChK2
Phosphorylated p53 is active as a _____ ____ that regulates the transcription of Cdk inhibitor ______
*Note at ATM phosphorylates ChK2 when DNA damage is found, Both the ATM and the ChK2 phosphorylates the p53
As a result of DNA damage, there is ______ levels of p53, which leads to _______ levels of p21, which inhibits the _______. What is the effect?
Increase levels of p53
Increased levels of p21
P21 inhibits the Cdk2/cyclin E complex which causes G1 arrest
Ultimately, the phosphorylation of p53 as a result of DNA damage leads to _____arrest.
G1 through inhibition of Cdk2/cyclin E by p21
Why is p53 frequently found mutated in cancers?
Because the mutated p53 would not be able to be phosphorylated in response to damage so it would not promote the synthesis of the Cdk inhibitor p21. Which means the the cell cycle would not be arrested in G1 despite the present of DNA damage which would increase the likelihood of damaged DNA in the daughter cell
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