Lecture 37 Cell Cycle Control and Cell Division Flashcards
1
Q
What does the cell cycle involve?
A
- DNA replication and dividing the cell to create two identical daughter cells
2
Q
What triggers the major events of the cell cycle?
A
- the cell cycle control system
3
Q
What controls cell proliferation?
A
- cell cycle control machinery
4
Q
What is cancer essentially?
A
- uncontrolled proliferation
5
Q
What are the three checkpoints in the cell cycle?
A
- start checkpoint
- G2/M checkpoint
- Metaphase to anaphase transition
6
Q
What does the start check point ask?
A
- is the environment favorable
7
Q
What does the G2/M checkpoint?
A
- is all the DNA replicated
- Is environment favorable?
8
Q
What does the metaphase to anaphase transition checkpoint ask?
A
- are all the chromosomes attached to the spindle
9
Q
what happens at the start checkpoint if its cleared?
A
- enter cell cycle and proceed to S phase
10
Q
What happens after G2/M phase?
A
- enter mitosis
11
Q
what happens after the metaphase to anaphase transition?
A
- trigger anaphase and proceed to cytokinesis
12
Q
What does the checkpoint system depend on?
A
- cyclin dependent protein kinases (Cdks)
- proteolytic events (protein degredation)
- Transcriptional regualtion (kinases)
13
Q
Essentially what is the cell cycle control system doing?
A
- arrests the cycle whenever the cell fails to complete essential cell-cycle process or encounters unfavorable intracellular or extracellular conditions
14
Q
G0 phase
A
- resting phase
- cells can permanently enter this resting phase (osteocytes)
- terminally differentiated cells
15
Q
What requires the the binding of cyclin and subsequent specific phosphorylation to become an active enzyme?
A
- cyclin dependent kinase (Cdk)
16
Q
In the absence of cyclin, cdk is _____?
A
- inactive
17
Q
What cyclin moves the cycle into S phase?
A
- G1/S
18
Q
What cyclin moves it through the S phase all the way to M phase?
A
- s-cyclin
19
Q
What cyclin moves the cycle through anaphase?
A
- M- cyclin
20
Q
Do the concentrations of Cdk change throughout the cell cycle?
A
- no
- constitutive expression
21
Q
What is critical for determining the transitions from one phase of the cell cycle to the next?
A
- the appearance and disappearance of the various cyclins
22
Q
What initiates the metaphase to anaphase transition?
A
- anaphase promoting complex or cyclosome or (APC/C)
23
Q
What moves the t loop away from the active site on cdk?
A
- cyclin binding
24
Q
When the t-loop binds the cdk is now _____ active?
A
- partially active
25
What enzyme acts to fully activate cdk?
- cdk-activating kinase
26
When is cdk fully active?
- when the t-loop is phosphorylated
27
What is the prerequisite for downstream events of the cell cycle?
- activation of the cyclin-cdk complex
28
Once cyclin-cdk is activated does the cell cycle proceed no matter what (uninterrupted)?
- no there are other regulatory factors downstream
29
What could a mutation of the regulatory factor lead to?
- potentially cancer
| - just like mutations to cyclin or cdk function could lead to misregulation of the cell cycle
30
What happens when Wee1 kinase adds a second phosphate to active cdk?
- it inactivates cdk
31
What enzyme is used to removed a 2nd phosphate and activate cdk?
- Cdc25 phosphatase
32
the apc/c is a member of the ____ ligase family of proteins
- ubiquitin
33
What is the function of APC/C?
catalyzes the ubiquitylation and degradation of securin and the S and M cyclins
34
What does securin do?
- securin is involved in the protein linkages that hold the sister chromatids together
35
What does securin degredation lead to?
- securin degradation leads to activation of a protease that then separates the sisters and unleashes anaphase
36
What does degredation of the S and M cyclins lead to?
- inactivation of the cdks
37
What does loss of cdks mean?
- that their targets can be dephosphorrylated by various phosphatases that are present in anaphase which completesM phase
38
When is APC/C activated?
- mid-mitosis
39
When is APC/C turned off?
- when G1/S-Cdks are activated in late G1?
| - this allows for cyclin accumulation to start the next cell cycle
40
What activates APC/C?
- cdc20
41
How does APC/C inactivate m-cyclin?
- it attaches a polyubiquitin chain that is targeted for protein degradation
42
What does SCF do?
- it ubiquitylates cdk inhibitor (CKI) proteins in late G1 such as p27
- (leads to activation of cell cycle)
43
What is p27?
-it is a CKI family member that binds to active cyclin-cdk complex
44
How does p27 make cdk complex innefecgtive?
- it distorts the active site of Cdk and also inserts into the ATP binding site, further inhibiting the enzyme activity
45
What is E1 and E2 role in degradation of CKI?
- they assist in the additoon of multiple ubiquitin molecules to the CKI and this targets the protein for degradation in the proteosome complex
46
What part of SCF complex binds to CKI?
- f box protein is required for binding to specific protein targets
47
What is the central component of the control system?
- the series of cyclin-cdk complexes that regulate transitions through the various phases
48
What is the inhibitory mechanisms role in cell cycle control?
- provide information about the extracellular environment, DNA or cell damage, and whether each step in the cell-cycle has been properly completed.
49
Is cyclin gene expression induced?
yes it is induced as the cell cycle transitions from one phase to the next
50
Three key steps of cycle
1. Induction of cyclins
2. Proteolysis
3. Transcriptional regulation
51
What would DNA damage during the cell cycle lead to?
- inhibitory mechanisms shutting the cycle down
52
Why does G0 typically occur?
- due to a lack of growth factors that a cell needs for the cell cycle
53
When does G0 occur?
- when cells reach maturity (some cells stay forever in this stage)
54
What does the dREAM complex do?
- binds exclusively to deacteylated histone
55
What does E2F promote?
- transcription
56
Co-repressors of either E2F and pRB lead to:
- histone modifications that result in histone compaction and suppression of gene expression
57
what is the cell cycle control system designed to do?
- block progression through each of the checkpoints if problems are sensed
58
Does DNA replication occur at random or specific sites?
- at specific sites or origins of replication
59
What two steps is the initiation phase of DNA replication divided into?
- Late mitosis-early G1: pre replication complex at the origins of replication
- Onset of S phase when pre replication complex nucleates the formation of the pre initiation complex
60
What are the parts of the prereplicative complex?
- ORC
- Cdc6 + Cdt1
- Mcm (helicase)
61
What is the initial step of S phase?
- degredation of phosphorylated Cdc6
| - inhibition of Cdt1 by geminin
62
what triggers the initial step of S phase?
- S- Cdk accumilation
63
What is the second step of the s phase?
- phosphorylation of ORC
| - and binding of pre initiation complex (DNA polymerase)
64
What is one of apcc role on late g2/m in regards to cdt1?
- degrades geminin so that we can form the prereplicative complex again and keep replicating
65
What leads to the formation of the pre initiation complex and initiation?
- s-Cdk activation
66
What does M-cdk activation lead to?
- chromosome segregation
67
What checkpoint insures that all of the DNA has been properly replicated?
- G2-M checkpoint
68
What drives entry into mitosis?
- abrupt increases in M-Cdk activity at the G2-M checkpoint
69
What does M-cdk induce?
- assembly of mitotic spindle
- chromosome condensation
- promotes break down of the nuclear envelop
- rearrangements of the actin cytoskeleton and the golgi apparatus
70
Mitosis (1 hour) comprises five phases
- prophase
- prometaphase
- metaphase
- anaphase
- telophase
71
What happens in prohpase?
- condensing replicated chromosome
- mitotic spindle forms
- centrosomes moving towards pole
72
What attaches to the mitotic spindle?
- kinetochore
73
What happens in prometaphse?
- breakdown of nuclear envelope
| - chromosomes attach and start to align
74
What happens in metaphase?
- chromosomes align at equator
| - everything lines up
75
What happens anaphase?
- the sister chromatids synchronously began to separate to form two daughter chromosomes.
- microtubules are getting shorter
-
76
What happens at telophase?
- daughter chromosomes arrive at poles
- begin to decondense
- nuclear envelope reassembles
- contractile rings form
77
What happens in cytokinesis?
- separation of two daughter cells
78
What is ESCO2 role in the cell cycle?
- it encodes an acetyltransferase that is important for the formation of the cohesion complex that binds to chromosomes and creates cohesion between sister chromatids
79
What happens with ESCO2 mutations?
- lead to decreased DNA transcription and subsequent ribosomal biogenesis and the observed defects in nuclear morphology
- leads to decreased protein synthesis
- roberts syndrome
80
what type of feedback does active M-cdk have on Cdc25 and Wee1?
- positive on both leading to more active M-cdk ?
81
What happens when securin is degraded?
- seperase is freed and activated and seperates chromatids by degraded adhesion proteins
82
what stimulates cell division?
mitogens
83
Mitogens
- stimulate cell division mainly by stimulating G1/S-Cdk activity that inhibit intracellular negative controls that block progression through the cell cycle
84
What do growth factors do?
- stimulate cell growth(increase in cell mass) by stimulating protein synthesis and inhibiting protein degradation
85
What do survival factors do?
- suppress programmed cell death (apoptosis)
86
How do mitogens trigger multiple intracellular signaling pathways?
1. mitogen binds to mitogen membrance ceptor
2. receptor activates ras
3. ras activates MAP kinase
4. activationn of gene regulatory protein
5. immediate early gene expression
87
what does immediate early gene expression lead to?
- gene regulatory proeteins like Myc
88
What does myc do?
- myc is thought to promote cell cycle entry by increasing the expression of the genes encoding the G1 cyclins which results in increased G1-Cdk activity
89
What does G1-cdk do in regards to regulation of cell cycle?
- activates regulatory factors like E2F
90
What inhibits E2F?
- retinoblastoma protein
91
How does G1-Cdk activate E2F?
- it phosphorylates Rb rendering it inactive and reducing its binding to E2F
92
What does E2F do?
- drive S phase gene transcription
- positive feed back on itself by phosphorylating rb
- also synthesizes and activates S-Cdk
93
What do growth factors do?
- stimulate protein synthesis and or protein degradation
94
What is epidermal growth factor signaling related to?
- PI3 kinase/Akt signaling
95
What protein does TGFB use?
- smad protein
96
What is smad protein target?
- p21
- p15
(smad inhibits cyclins)
97
TOR
- gene regulatory factors
- ribosome synthesis
- protein synthesis and cell growth
