Cell Cycle Control Flashcards
(81 cards)
1
Q
3 states in cell cycle:
A
Quiescent
Interphase
Mitosis
2
Q
4 phases in cell cycle:
A
(G0)
G1 = Growth, Preparation for DNA synthesis
S = DNA replication
G2 = Preparation for mitosis, Growth
M = PMAT
3
Q
Also known as senescence state, comprises of the G0 phase. Examples: Neurons, cardiac muscle and RBCs.
A
Quiescent stage
4
Q
Interphase state comprises of these phases
A
G1, S, and G2 phases
5
Q
Mitosis state consists of the _____
A
M phase = PMAT
6
Q
3 major cell cycle checkpoints:
A
End of G1
End of G2
Metaphase of M phase
7
Q
Progression through checkpoints is regulated by the following:
A
Cyclins
Cyclin-Dependent Kinases (CDKs)
Tumor Suppressors
8
Q
During the G1 phase, cell cycle progression is controlled by a variety of different cellular mechanisms such as ___________, __________, _______ that affect DNA damage, _________ that allow the cell to progress to the S phase, and __________ that activate those enzymes.
A
- Tumor suppressors
- Transcription genes
- Proteins
- Enzymes
- Signaling molecules
9
Q
Which gene regulates the expression of transcription genes, CDKs, Cyclin E, and Cyclin A.
A
Gene E2F
10
Q
If there is significant DNA damage, _____ stimulates production of _____. —– binds and inhibits all Cyclin - CDK complexes which leads to arrest of cell cycle until the DNA damage is repaired and —– levels drop.
A
p53; p21
11
Q
The tumor suppressor, ________, inhibits E2F expression. Cyclin D - CDK 4 and Cyclin D - CDK 6 complexes phosphorylate ——— that leads to inactivation of ——– and and expression of E2F. The expression of E2F then leads to the expression of transcription genes and formation of Cyclin E - CDK 2, therefore the cell is pushed into the S phase.
A
retinoblastoma protein
12
Q
Cell cycle regulation in S and M phase:
________ is required for DNA synthesis. Cyclin A - CDK 1 and Cyclin B - CDK 1 promotes the events of mitosis. Towards the end of mitosis, the __________, causes ubiquitination and destruction of Cyclin A - CDK 1 and Cyclin B - CDK 1 that leads to termination of M phase with anaphase, telophase, and cytokinesis.
A
Cyclin A - CDK 2; anaphase promoting complex
13
Q
The most radiosensitive phases are the _____ and _____
A
G2 phase; mitosis
14
Q
The least radiosensitive phase is the _____
A
latter part of the S phase
15
Q
Why do cells divide?
A
- Grow in size
- To replace old and damaged cells
- Reproduction
16
Q
Categories of cells
A
- Cells that no longer divide after they differentiate = parasympathetic neurons
- Cells that normally don’t divide but can be induced to divide w/ proper stimulus (liver cells, lymphocytes)
- Cells with relatively high level of mitotic ability (stratum germinativum of skin, tunica mucosa of intestine, meristematic tissues of plants = Apical meristem, Intercalary meristem, & Lateral meristem)
17
Q
a type of white blood cell that plays a crucial role in the immune system, helping the body fight infections and diseases
A
Lymphocytes
18
Q
Each step of the cell cycle is monitored by internal control, called ________. They are like a gatekeeper of the cell cycle.
A
Checkpoints
Checkpoint control system
* Checkpoints
* cell cycle controlled by STOP & GO chemical signals at critical points
* signals indicate if key cellular processes have been completed correctly
19
Q
Which checkpoint control system?
- Ensures the environment is favorable for DNA replication
- Cell size
A
G1/S: restriction point
20
Q
Which checkpoint control system?
- Checks for DNA damage and ensures replication is complete
A
G2/M
21
Q
Which checkpoint control system?
- Ensures all chromosomes are properly attached to the mitotic spindle before separation
A
Metaphase/Anaphase checkpoint (spindle checkpoint)
22
Q
Major Players of Cell Cycle
A
- Cyclin
- Cdks (cyclin-dependent protein kinase)
23
Q
Major Players of Cell Cycle
- regulatory subunit
- Constant cycle of synthesis and degradation during cell division
- Activates Cdks and thereby help control progression from 1 stage of the cell cycle to the next
A
Cyclin
24
Q
Major Players of Cell Cycle
- Dependent on cyclin
- catalytic subunit
- Enzyme that adds negatively charged phosphate groups to other molecules (________), which indicates that the cell is ready to pass into the next stage of the cell cycle
A
- Cdks (cyclin-dependent protein
kinase);
phosphorylation
25
In vertebrates, the Cyclin-Cdk complex as G1-Cdk is
Cyclin D + Cdk4, Cdk6
= Commit the cell to DNA replication
26
In vertebrates, the Cyclin-Cdk complex as G1/S-Cdk (R point [late G1 - Restriction point]) is
Cyclin E + Cdk2
= Help promote passage thru restriction point in late G1
27
In vertebrates, the Cyclin-Cdk complex as S-Cdk is
Cyclin A + Cdk2, (Cdk1**)
= Ensures DNA is copied once and only once
28
In vertebrates, the Cyclin-Cdk complex as M-Cdk is
Cyclin B + Cdk1 (cdc2)
= Maturation promoting factor
= Promote the events of mitosis
29
In budding yeast, the Cyclin-Cdk complex as G1-Cdk is
Cln3
Cdk 1**
30
In budding yeast, the Cyclin-Cdk complex as G1/S-Cdk is
Cln 1, 2
Cdk 1
31
In budding yeast, the Cyclin-Cdk complex as S-Cdk is
Cln5, 6
Cdk 1
32
In budding yeast, the Cyclin-Cdk complex as M-Cdk is
Clb 1, 2, 3, 4
Cdk 1
33
There are 3 D cyclins in mammals:
Cyclins D1, D2, and D3
34
The original name of Cdk1 was _____ in vertebrates and fission yeast, and _____ in budding yeast
Cdc2; Cdc28
35
Concentration of the cyclin proteins change throughout the cell cycle. There is a direct correlation between cyclin accumulation and 3 major cell cycle checkpoints. Cyclin expression levels are not constant, rather, cyclins are again synthesized and degraded in a tightly regulated cell cycle dependent manner.
36
The concentrations of the three major cyclin types oscillate during the cell cycle, while the concentrations of Cdks (not shown) exceed cyclin amounts and do not change.
37
* phosphorylates an activating site in Cdks
Cdk-activating kinase (CAK)
A. Inactive = Cdk
+ Cyclin
B. Partially active
+Cdk-activating kinase (CAK)
C. Fully active
38
Kinase = attaches phosphate
Phosphatases = removes phosphates
39
The binding of cyclin causes the T-loop to move out of the active site, resulting in partial activation of Cdk2. Phosphorylation of Cdk2 (by CAK) at a threonine residue in the T-loop further activates the enzyme by changing the shape of the T-loop, improving the ability of the enzyme to bind its protein substrates
40
Protein phosphatases that modify Cdks
* Wee1 kinase
- phosphorylates inhibitory sites in Cdks; primarily involved in controlling entry into mitosis
* Cdc25 phosphatase:
- removes inhibitory phosphates from Cdks
41
Phosphatases decrease when cdk activity increases
________
* Dephosphorylates of Cdc25 and Wee1 during anaphase and telophase
Protein phosphatase 2 (PP2A)
= high during interphase but inhibited during mitosis when M-Cdk activity rises.
42
Control of PP2A-B55 activity in mitosis. Prior to mitosis, PP2A-B55 is active, helping to reduce the phosphorylation of M-Cdk targets. When M-Cdk activity begins to rise at the beginning of mitosis, it phosphorylates and thereby activates another protein kinase called Greatwall. This kinase in turn phosphorylates a small protein called Ensa, which binds tightly to PP2A-B55 and inhibits phosphatase activity. M-Cdk thereby inactivates its opponent. As an added twist, PP2A-B55 can dephosphorylate Greatwall (dashed line), thereby inhibiting its own inhibitor—a form of positive feedback. We discuss the implications of this feedback in a later section.
43
_____ is the one that adds inhibitory phosphate in the Cdk-Cyclin complex. And ______ is the one that remove the inhibitory phosphate that is added by ------.
Wee1; Cdc25
44
Key Components and Processes:
Cdk + M-cyclin = Inactive M-Cdk complex
Cdk binds to M-cyclin, forming an inactive M-Cdk complex.
This complex is kept inactive due to inhibitory phosphorylation.
Phosphorylation by CAK and Wee1:
CAK (Cdk-activating kinase) adds an activating phosphate.
Wee1 kinase adds an inhibitory phosphate.
Despite the activating phosphate, the complex remains inactive as long as the inhibitory phosphate is present.
Activation by Cdc25 phosphatase:
Cdc25 removes the inhibitory phosphate, resulting in active M-Cdk.
This triggers entry into mitosis.
Positive Feedback Loops:
Active M-Cdk enhances Cdc25 activity (activating its own activator).
Active M-Cdk inhibits Wee1 (inhibiting its own inhibitor).
These positive feedback loops sharpen the switch-like activation of M-Cdk, leading to a rapid and decisive commitment to mitosis.
PP2A-B55 phosphatase:
PP2A-B55 counteracts Cdc25 and maintains inactivity by dephosphorylating multiple substrates.
Its own activity is regulated indirectly in this system to ensure timing coordination.
45
____ monitors a cyclin, a protein kinase and a protein phosphatase
Cdk
46
Cdk inhibitory proteins (CKIs)
1. p27
- Suppresses G1/S-Cdk and S-Cdk activities in G1;
- Helps cells to withdraw from cell cycle when they terminally differentiate
2. p21
- Suppresses G1/S-Cdk and S-Cdk activities following DNA damage in G1;
- transcriptionally activated by p53
3. p53
- Tumor suppressor
- Promotes transcription of genes that induce cell cycle arrest or apoptosis in response to DNA damage or other cell stress
- Regulated by Mdm2
- Promotes DNA degradation
- Cells would stop at G1/S
47
* Is the addition of ubiquitin molecule residues of a protein directing the proteins for degradation via the proteasome or by lysosomes
* Involves ubiquitin ligases
Ubiquitination
48
* Catalyzes ubiquitylation of securin and S-cyclins and M-cyclins
APC/C (anaphase promoting complex or cyclosome)
49
The control of proteolysis by the APC/C. The APC/C is activated in metaphase by association with Cdc20, which recognizes specific amino acid sequences on M-cyclin and other target proteins. With the help of two additional proteins called E1 and E2 (see Chapter 3), the APC/C assembles polyubiquitin chains on the target protein. The polyubiquitylated target is then recognized and degraded in a proteasome.
50
When is APC/C active?
2 phases:
- At the Metaphase-Anaphase transition
- Throughout G1 phase
51
* APC/C-activating subunit in all cells
* Triggers initial activation of APC/C at metaphase-to-anaphase transition, stimulated by M-Cdk activity
cdc20
52
Sequential activation of APC/C by Cdc20 and Cdh1. M-Cdk phosphorylates the APC/C, thereby enhancing its association with Cdc20. Thus, M-Cdk not only triggers the early mitotic events leading up to metaphase, but it also sets the stage for progression into anaphase and the destruction of cyclins. This creates a negative feedback loop: M-Cdk sets in motion a regulatory process that leads to its own inactivation. More negative feedback then follows: APC/C-Cdc20 also turns itself off by inactivating Cdks, which allows APC/C dephosphorylation. APC/C-Cdc20 is thereby inactivated in anaphase. The APC/C remains active through mitosis and beyond because the second activator, Cdh1, is regulated in a completely different fashion: Cdh1 phosphorylation by Cdks inhibits its binding to the APC/C, keeping it inactive from late G1 to anaphase. When cyclins are destroyed in anaphase, Cdk inactivation allows Cdh1 dephosphorylation, which activates Cdh1 and thereby stimulates formation of APC/C-Cdh1. APC/C-Cdh1 remains active until Cdh1 is phosphorylated and thereby inactivated by G1/S- and S-Cdks at the beginning of the next cell cycle.
53
Cdc also triggers the destruction of securin and cyclin resulting in chromosome segragation in anaphase.
54
* Binds into and inhibits the activity of separase
Securin
55
Cleave subunit of cohesin separating the sister chromatids
Separase
56
* APC/C activating subunit that maintains APC/C activity after anaphase and throughout G1
* Inhibited by Cdk activity
cdh1
57
Catalyzes ubiquitylation of regulatory proteins involved in G1 control, including CKIs
SCF (Skp, Cullin, F-box containing complex)
58
pRB-E2F pathway
- pRB serves as a break in cell cycle by binding to E2F
Inactivation (hyperphosphorylation) of pRB helps switch the progress of the cell cycle to mitosis
- Phosphorylation inactivates pRB since it cannot bind to E2F
59
- Genes that promote transcription of genes required for G1/S progression
- Binds with Cdk and Cyclin A producing the S promoting factor
E2F
60
THREE PROCESSES THAT DETERMINE CELL SIZE
1. Cell Growth
2. Cell Division
3. Cell Survival
61
Process that results from a variety of stresses and leads to a state of irreversible growth arrest.
Cellular senescence
62
SIGNAL MOLECULES THAT REGULATE CELL GROWTH, DIVISION AND SURVIVAL
* MITOGEN
* GROWTH FACTORS
* SURVIVAL FACTORS
63
* Stimulates cell division
* Triggers G1/S-Cdk activity that relieves negative controls of cell cycle
Mitogen
64
* Stimulates cell growth (an increase in cell mass) by promoting the synthesis of proteins and other macromolecules
GROWTH FACTORS
65
* Promote cell survival by suppressing programmed cell death
SURVIVAL FACTORS
66
- Tumor suppressor protein that serve as the guardian of the restriction-point gate
- Prevents excessive cell growth by inhibiting cell cycle progreession until a cell is ready to divide
Retinoblastoma protein
67
Mitogen stimulation of cellcycle entry. As discussed in Chapter 15, mitogens bind to cell-surface receptors to initiate intracellular signaling pathways. One of the major pathways involves activation of the small GTPase Ras, which activates a MAP kinase cascade, leading to increased expression of numerous immediate early genes, including the gene encoding the transcription regulatory protein Myc. Myc increases the expression of many delayedresponse genes, including some that lead to increased G1-Cdk activity (cyclin DCdk4), which triggers the phosphorylation of members of the Rb family of proteins. This inactivates the Rb proteins, freeing the gene regulatory protein E2F to activate the transcription of G1/S genes, including the genes for a G1/S-cyclin (cyclin E) and S-cyclin (cyclin A). The resulting G1/S-Cdk and S-Cdk activities further enhance Rb protein phosphorylation, forming a positive feedback loop. E2F proteins also stimulate the transcription of their own genes, forming another positive feedback loop.
68
Several ways for cell to grow or to divide:
A. Extracellular growth -> Cell growth -> Cell division
B. Growth factor -> Cell growth
+
Mitogen -> Cell division
C. Extracellular factor -> Cell growth & Cell division
69
MITOGENS THAT STIMULATE CELL DIVISION
1. PLATELET-DERIVED GROWTH FACTOR (PDGF)
* Stimulate cells to divide, such as fibroblasts, smooth muscle cells and neuroglial cells
2. EPIDERMAL GROWTH FACTOR (EGF)
* Acts on epithelial and nonepithelial cells
3. ERYTHROPOIETIN
* Induces the proliferation of red blood cells
4. TRANSFORMING GROWTH FACTOR-ẞ (TGF- ẞ)
* Inhibits the proliferation of several cells by blocking cell-cycle progression
70
Family of proto-oncogenes and transcription factors that promote cell cycle by increasing the expression of genes encoding G1-cyclins
Myc
71
quantitative colorimetric method to determine the cell proliferation.
* utilizes the yellow tetrazolium salt (3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium- bromide) which is metabolized by mitochondrial succinic dehydrogenase activity of proliferating cells to yield a purple formazan product by the mitochondria of viable cell
*Measure the absorbance using spectrophotometry
= The cell is alive if the color of MTT is yellow and the color is converted into purple - Positive result
= yellow means dead
MTT assay
72
Which protein directly activates Cdks during the cell cycle?
Cyclins
73
What happens if a cell fails the G1/S checkpoint?
➡️ It undergoes cell cycle arrest or goes to G0
74
Which of the following complexes triggers the cell's entry into mitosis?
➡️ Cyclin B/Cdk1
75
Which of the following events is a signal that allows a cell to proceed from metaphase to anaphase?
➡️ Activation of APC/C leading to degradation of securin
76
What is the main function of protein phosphatase 2A (PP2A)?
➡️ To remove phosphate groups from proteins
77
Cyclin expression is constant throughout the cell cycle, as to regulate the expression of Cdks. True or False
➡️ False
(Cyclin levels fluctuate; they are synthesized and degraded in specific phases.)
78
Which cyclin regulates the commitment to cell division in response to extracellular signals?
➡️ Cyclin D
79
Which of the following degrades securin?
➡️ APC/C
80
Which of the following is the guardian of the restriction-point gate?
➡️ Retinoblastoma protein
81
p53 exerts its effects by inducing the expression of which of the following proteins?
➡️ p21
