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Cancer, Cell communication and the Cell Cycle
I. Cell Cycle – Chapter 18
You will not be responsible for:
details of S-CdK function
mechanisms of spindle assembly and anaphase
specific details of the caspase cascade & bcl-2 family
topics on extracellular signals (pp 636- 640) not covered in class
Review mitosis on your own  Panel 18-1, etc
Read on your own about cytokinesis
in plant and animal cells pp 630 - 633
Questions in this chapter you should be able to answer:
Chapter 18: 1 - 5, 10, 12, 13, 14, 16, 17, 20, 25, 26 all but C, 28, 30
Cancer and Cell Cycle Regulation
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What are the stages of the cell-cycle?
-- a review
G1
S
G2
M
G0
Table 18–1 Some Eucaryotic Cell-Cycle Times
Cell type
Cell cycle time
Early frog embryo cells
~30 minutes
Yeast cells
1.5–3 hours
Intestinal epithelial cells
~12 hours
cultured fibroblasts
~20 hours
Human liver cells
~1 year
Cancer and Cell Cycle Regulation
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Tumor suppressor proteins are
‘Gatekeepers’ and ‘Caretakers’
of the cell
Stop
Go
Die
Cancer and Cell Cycle Regulation
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Mutated Tumor Suppressor Genes disable
the corresponding Tumor Suppressor Proteins . . .
Cells divide
when they
shouldn’t
Cells do not die
when they
should
Cells progress
toward metastasis
Cancer and Cell Cycle Regulation
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Cells of cancers accumulate numerous
chromosomal abnormalities
Meningioma karyotype
Deletions
Aneuploidy - #s 7, 9, 20
Missing homolog - #1, 17, Y
Translocations - #s 2, 6, 7
Translocations
Inversions
Duplications
Should trigger
apoptosis
Tick and Sick-6
5
Some examples of inactivated Tumor Suppressor
Proteins and Oncogenes
Tick and Sick-6
6
Tumor Suppressor Proteins are part of the
“Cell-cycle Control System”
The ‘Checkpoint’ model
How are they controlled?
-- intracellular and extracellular signals
What are the effectors
-- lots of kinases & phosphatases
Cancer and Cell Cycle Regulation
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How is cell cycle progress
studied?
Different systems
-- yeast: cell cycle mutations
-- frog: big dividing embryos
-- sea urchin & clam: many embryos
Asynchronously dividing cells
DNA/nucleus staining
Flow cytometry
DAPI stained cells
Ques 18-2
Where are
G1,S,G2, & M
stage cells?
Synchronously dividing cells
Cancer and Cell Cycle Regulation
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What did study of frog embryos reveal about the control
system?
Be sure to read
How we know
Frog egg cytoplasmic
transfer experiments
Something in the cytosol
triggers mitosis
-- called MPF
Activity of MPF oscillates
during the cell cycle
What is MPF?
Cancer and Cell Cycle Regulation
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What did sea urchin &
clam embryos reveal?
Population of synchronously
dividing embryos
S35 labeling, SDS-PAGE,
autoradiography
Revealed cyclic synthesis &
breakdown of certain proteins
Called cyclin
Cancer and Cell Cycle Regulation
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What do we know about
MPF & cyclin?
MPF is a cyclin bound to a Cdk
‘cyclin-dependent protein kinase’
Table 18–2 The Major Cyclins and Cdks
of Vertebrates
= M-Cdk
Cyclin–Cdk Complex
Several Cyclins and Cdks
-- regulate different cell cycle events
G1-Cdk
G1/S-Cdk
S-Cdk
M-Cdk
Cancer and Cell Cycle Regulation
Cyclin
cyclin D
cyclin E
cyclin A
cyclin B
Cdk partner
Cdk4, Cdk6
Cdk2
Cdk2
Cdk1
11
How is cyclin-CDK
activity regulated?
Two processes
1. Synthesis &
destruction of cyclin
-- ubiquination
-- proteasomes
2. Inactivation & activation
-- Activating/inhibitory Kinases/phosphatase
-- Pos feedback  rapid activation
Cancer and Cell Cycle Regulation
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How do cyclin-cdk’s trigger
cellular events?
S-Cdk triggers DNA replication
-- activates replication origins
-- blocks reactivation
What does activated M-CDK do?
1)
2)
3)
4)
Phosphorylates H1 histone
(triggering C’some condensation)
Disassembly of nuclear lamina
Changes behavior of microtubules
-- phosphorylates MAPs
etc…??
Cancer and Cell Cycle Regulation
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How does activated S-Cdk trigger DNA replication?
Origin of Replication Complex (ORC)
CDC-6 rises during G1
-- helps build replication fork complex
-- helicase, polymerase, etc
S-CDK activates replication complex
-- inhibits ORC
Cancer and Cell Cycle Regulation
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Figures 18-14 + 18-15
How do checkpoint proteins
(i.e.,TSPs) suppress cell
division?
P53, BRCA1, P21 and Rb are all TSPs
-- loss of both alleles necessary
Why?
P53 can also trigger apoptosis
Cancer and Cell Cycle Regulation
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What are the mechanisms of apoptosis activation and
cellular destruction?
Intrinsic activation signals
-- cell injury, P53 activation, etc
-- lack of survival signal
Intrinsic vs extrinsic activation
Caspase family of proteases
-- activation ‘cascade’
Extrinsic activation signals
-- cell-surface receptors (Fas/FasL)
-- cellular toxins (Granzymes)
Caspase cascade
Intrinsic pathway
Question 18-10, p 635
Why apoptosis rather than
necrosis?
Cancer and Cell Cycle Regulation
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