PRIVETTE-VINNEDGE 1 Flashcards
1
Q
What is the cell cycle?
A
The regulated process by which a cell replicates its contents and divides into two daughter cells, also known as cell proliferation.
2
Q
Are all cells in a population actively dividing in the cell cycle?
A
No, not all cells are actively dividing.
3
Q
How are the transitions between cell cycle phases controlled?
A
Transitions are molecularly controlled by external and internal feedback mechanisms.
4
Q
What is a consequence of cell cycle regulation disruption?
A
It contributes to diseases like cancer.
5
Q
What are the two states of cells that are not actively dividing?
A
Senescence and quiescence.
6
Q
Define senescent cells.
A
They have permanently stopped cycling and do not respond to proliferative stimuli but remain metabolically active.
7
Q
What triggers cellular senescence?
A
Stress factors like radiation, DNA damage, telomere shortening, organelle dysfunction, and oncogene activation.
8
Q
Who discovered cellular senescence and what is it called?
A
Leonard Hayflick and Paul Moorhead in 1961, called the Hayflick limit.
9
Q
What are p21 and p16?
A
Inhibitors of the cell cycle; they express senescent associated glycosidase.
10
Q
How was the Hayflick limit discovered?
A
Found out that normal human fibroblasts stop proliferating after 40-60 doublings when serially passaged
11
Q
Name a marker of senescence.
A
Expression of senescence-associated beta-galactosidase, causing cells to turn blue in a beta-gal assay.
12
Q
p53 is termed “Guardian of the _________.”
A
Genome
13
Q
What are two other markers of senescence?
A
Increased expression of p16 and p21 proteins.
14
Q
What is SASP?
A
Senescence-associated secretory phenotype, where cells secrete factors that can impact surrounding tissues.
15
Q
What is a central trigger of senescence?
A
Chronic activation of p53 by cellular stress.
16
Q
How do p21 and p16 function in the cell cycle?
A
They inhibit cyclin-dependent kinases (CDKs) and block cell cycle entry.
17
Q
What happens when p53, p21, or p16 are mutated or have decreased expression?
A
Cells can escape senescence and proliferate despite stress, which is often seen in cancer.
18
Q
What is another name for quiescence?
A
G0 phase of the cell cycle.
19
Q
Describe quiescent cells.
A
They are not cycling but can enter the cell cycle upon stimulation.
20
Q
Provide examples of stimuli that cause quiescent cells to re-enter the cell cycle.
A
Tissue injury and infection.
21
Q
List cell types that can be quiescent.
A
Stem and progenitor cells, lymphocytes, fibroblasts, and hepatocytes.
22
Q
True or False: It can be difficult to determine if a cell is in G0 or G1.
A
True
23
Q
What is a marker of quiescence?
A
Low RNA levels (Pyronin Y) compared to DNA levels (Hoechst); Reduced metabolic activity; High expression of CDK inhibitors (p27, p21)
24
Q
How many phases of preparation for cell division are there in interphase?
A
Three
25
What are the growth phases in the cell cycle?
G1 and G2
26
G0 has a ______(low/high) ratio of RNA to DNA, while G1 has a _______(low/high) ratio of RNA to DNA.
low, high
27
What are the growth phases in the cell cycle?
G1 and G2
28
What happens during S phase?
DNA replication (synthesis)
29
What is the M phase and what happens during it?
Mitosis, where cell division occurs.
30
What makes G2 different from G1?
G2 has proofreading of the replicated DNA from S phase because the cell is preparing for mitosis.
31
What regulates transitions between cell cycle phases?
Tightly regulated by cell cycle checkpoints
32
What triggers quiescent cells to exit G0?
Extracellular growth factors or other stimuli.
33
Give examples of stimuli that trigger specific cell types to leave quiescence.
T cells are stimulated by antigen-presenting dendritic cells, and tissue stem cells proliferate in response to injury and wound healing signals.
34
How do extracellular growth factors induce cell cycle entry and proliferation?
By stimulating the PI3K/Akt/mTOR pathway.
35
True or False: There are two mitotic checkpoints.
True
36
What role do DNA damage signaling and repair proteins play in quiescence?
They help maintain a quiescent state through p53 activation.
37
What are the requirements for cells to enter G1?
Pro-growth signals and the absence of damaged DNA signals.
38
Describe the G1 phase.
The gap between mitosis and the next round of DNA synthesis where the cell grows in size.
39
What is the importance of G1?
The cell relies on its synthesis pathways and extracellular nutrients, increasing metabolism and protein production for cell division.
40
Is the G1 phase always necessary?
No, cells can skip G1 if sufficient resources are available, like in embryonic cells that cycle M-S-M-S due to maternal nutrient stores in the egg.
41
Why is G1 important in metazoans?
It senses the environment before DNA replication to prevent replication without resources and ensures that replication benefits the organism.
42
True or False: p53 pathway must be inhibited for the cell to enter quiescence.
True, along with growth factors
43
What happens when G1 regulation goes awry?
It can lead to pre-cancerous hyperplasia.
44
What drives cell cycle progression?
Fluctuations in cyclin expression.
45
How do cyclin-CDK complexes regulate the cell cycle?
They phosphorylate target proteins, leading to changes in the cell cycle phase.
46
What was the significance of the discovery of cyclin/CDK complexes and cell cycle regulators?
It led to the 2001 Nobel Prize in Physiology and Medicine, awarded to Paul Nurse, Leland Hartwell, and Tim Hunt.
47
Which cyclin-CDK complex is involved in the G2 to M phase transition?
Cdk1 (Cdc2) with Cyclins A and B.
48
Which cyclin-CDK complexes are important in the G1 phase?
Cdk2 with Cyclins D1, D2, and D3, and Cdk4/6 with Cyclins D1, D2, and D3.
49
True or False: Early embryonic cells need a G1 phase.
False, only cells that need to produce their own nutrients need to have a G1 phase. Early embryonic cells have maternal environment providing their nutrients.
50
What are the three members of the cyclin D family?
D1, D2, D3
51
What is the current understanding of cyclin D2 and D3?
They're poorly characterized.
52
What are the characteristics of cyclin D family members?
Cell/tissue-specific expression and they all bind to CDK4/6.
53
How is cyclin D expression and function regulated?
Through transcriptional activation by upstream proliferation pathways and phosphorylation at Thr-286 by GSK3b, leading to nuclear export and degradation.
54
What is the role of CDK inhibitors (CDKIs)?
They block the kinase function of cyclin-dependent kinases and act as tumor suppressor proteins.
55
__________ is the process of going from a normal cell to a cancer cell.
Transformation
56
How many CDKIs have been identified and how are they named?
Seven, all starting with a small "p" followed by their molecular weight in kilodaltons.
57
CDK stands for _________.
Cyclin-dependent kinases
58
How is the expression of CDKIs regulated?
Through chromatin remodeling, histone modifications, and transcriptional regulators.
59
What is the target of the CDK4/6-Cyclin D complex?
The retinoblastoma (Rb) protein.
60
What is the function of the Rb protein and how does phosphorylation affect it?
Rb is a transcriptional repressor, and phosphorylation inactivates it, releasing E2F transcription factors, leading to cell cycle progression.
61
What is the effect of p16ink4a binding to CDK4 or CDK6?
It displaces cyclin D and inhibits kinase activity.
62
Name three CIP/KIP inhibitors.
p21Cip1 (Waf1), p27Kip1, and p57Kip2.
63
How do CIP/KIP inhibitors function?
They bind to CDK4/6-Cyclin D and CDK2-Cyclin E complexes, inhibiting CDK activity.
64
Describe the function of the Rb protein.
It acts as a transcriptional repressor.
65
What is the consequence of Rb protein phosphorylation?
Inactivation of Rb and release of E2F transcription factors, promoting cell cycle progression.
66
What role does Rb play in cancer development?
It is a tumor suppressor, and germline and somatic mutations in Rb contribute to tumorigenesis.
67
What happens when Rb is mutated and cannot be phosphorylated?
Cells experience a loss of S and G2/M populations, indicating cell cycle arrest.
68
How many E2F transcription factors are there?
There are six, E2F1-6.
69
How are E2F transcription factors inhibited?
By binding to unphosphorylated Rb.
70
What genes are regulated by E2F transcription factors?
Cell cycle genes and DNA replication genes, including cyclin E, cyclin A, and DNA polymerase.
71
How does the E2F-DP complex function in transcription?
It acts as a transcriptional activator.
72
How does the RB-E2F-DP complex function in transcription?
It acts as a transcriptional repressor.
73
What is a key molecular event in the G0-G1-S phase transition that is often dysregulated in cancers?
Deregulation of the Rb pathway, leading to uncontrolled cell proliferation.
74
What is a hallmark of cancer related to cell proliferation?
Uncontrolled cell proliferation, often due to cell cycle deregulation.
75
What is the mechanism of action of traditional chemotherapy?
It targets rapidly proliferating cells, killing both cancer cells and rapidly dividing normal cells
76
What are the common targets of traditional chemotherapy?
Cell structures or proteins involved in DNA replication or mitosis.
77
What is a next-generation approach to cancer therapy?
Small molecule kinase inhibitors.
78
Provide examples of CDK4/6 inhibitors.
Palbociclib, ribociclib, and abemaciclib.
79
What type of cancer are CDK4/6 inhibitors approved for?
ER/PR+ breast cancers.
80
Why is it essential to determine the Rb mutation status before using CDK4/6 inhibitors?
These inhibitors require functional, wild-type RB for efficacy.
81
What is the function of the DREAM complex?
It acts as a master regulator of cell cycle gene expression.
82
What are the components of the DREAM complex?
DP, Rb family, E2F4-5, and MuvB.
83
What is the role of the PI3K/Akt/mTOR pathway in cell cycle regulation?
Extracellular growth factors stimulate this pathway to induce cell cycle entry and proliferation.
84
Why do cells need pro-growth signals and the absence of DNA damage to enter G1?
Pro-growth signals indicate a favorable environment for growth, while the absence of DNA damage ensures that the cell's genetic material is intact before replication.
85
What are the potential consequences of G1 dysregulation?
Dysregulation of G1 can lead to uncontrolled cell proliferation and contribute to the development of cancer.
86
What is the difference between the function of Cyclin D-CDK4/6 and Cyclin E-CDK2 complexes?
Both complexes are active in G1, but Cyclin D-CDK4/6 primarily phosphorylates Rb, while Cyclin E-CDK2 is involved in the G1 to S phase transition.
87
What is the role of phosphorylation at Thr-286 by GSK3b in cyclin D regulation?
It targets cyclin D for nuclear export and degradation, signaling the transition to S phase and preventing immediate re-entry into G1 after mitosis.
88
How do environmental signals influence CDK inhibitor expression?
Factors like TGF-beta, DNA damage, and differentiation signals can induce the expression of CDK inhibitors like p16ink4a.
89
What is the significance of the CDK2NA/B locus in cell cycle regulation?
This locus encodes CDK inhibitors like p16ink4a, which play a crucial role in regulating the G1 to S phase transition.
90
How do Bmi1 and the polycomb repressive complex (PRC1) regulate the CDK2NA locus?
They ubiquitinate histone H2A, leading to the repression of CDK inhibitor expression.
91
What is the difference between the function of E2F as a transcriptional activator and repressor?
When bound to Rb, E2F acts as a repressor of cell cycle genes. When released from Rb, it acts as an activator, promoting the transcription of genes needed for S phase entry.
92
What are the implications of the fact that most traditional chemotherapy targets rapidly proliferating cells?
This non-specific targeting leads to side effects as it also affects rapidly dividing normal cells in tissues like the skin and intestines.
93
What is the advantage of using next-generation small molecule kinase inhibitors over traditional chemotherapy?
Kinase inhibitors, such as CDK4/6 inhibitors, offer more targeted therapy, potentially reducing side effects by specifically inhibiting key molecules driving cancer cell proliferation.
94
True or False: All cells in the body are actively dividing.
False, Some cells are in a quiescent (G0) or senescent state.
95
True or False: The cell cycle is tightly regulated.
True. Checkpoints and feedback mechanisms control transitions between phases.
96
True or False: Quiescent cells can never re-enter the cell cycle.
False. Quiescent cells can re-enter the cell cycle upon stimulation.
97
True or False: Senescent cells are dead.
False. Senescent cells are metabolically active but cannot divide.
98
True or False: CDK inhibitors promote cell cycle progression.
False. CDK inhibitors block the activity of cyclin-dependent kinases, inhibiting cell cycle progression.
99
True or False: Rb is an oncogene.
False. Rb is a tumor suppressor gene. Mutations in Rb can lead to cancer.
100
True or False: E2F transcription factors are always active.
False. E2F activity is regulated by Rb.
101
True or False: Cancer cells often exhibit dysregulation of the G1 to S phase transition.
True. Mutations in genes regulating this transition, such as Rb, are common in cancer.
102
What is the role of growth factors in the cell cycle?
Growth factors stimulate signaling pathways, like the PI3K/Akt/mTOR pathway, to promote cell cycle entry and progression.
103
What are the main differences between senescence and quiescence?
Senescence is a permanent state of cell cycle arrest often triggered by stress, while quiescence is a reversible state where cells are not dividing but can re-enter the cell cycle upon stimulation.
104
How can the cell cycle be therapeutically targeted for cancer treatment?
By using drugs that inhibit key molecules involved in cell cycle regulation, such as CDK inhibitors, which block the activity of CDKs, preventing cell cycle progression and tumor growth.
105
Why are CDK4/6 inhibitors effective in treating certain types of breast cancer?
CDK4/6 inhibitors target the cyclin D-CDK4/6 complex, which is essential for phosphorylating Rb and driving cell cycle progression. This inhibition is effective in ER/PR+ breast cancers where Rb function is intact.
106
What are the potential limitations of using CDK4/6 inhibitors in cancer therapy?
These inhibitors are only effective in cancers with wild-type Rb, as they rely on functional Rb for their therapeutic effect. Additionally, they may have side effects due to their impact on normal cell cycling.
107
What are future directions for developing more effective cell cycle-targeted therapies for cancer?
Further research is needed to identify more specific and potent inhibitors of key cell cycle regulators, to minimize side effects and overcome resistance mechanisms that cancer cells may develop. Additionally, exploring combination therapies that target multiple cell cycle pathways simultaneously could enhance treatment efficacy.
