The Cell Cycle and Mitosis Cell Cycle Interphase Mitosis Cytokinesis.
Cancer and Cell Cycle Regulation1 Cancer, Cell communication and the Cell Cycle I. Cell Cycle –...
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Transcript of Cancer and Cell Cycle Regulation1 Cancer, Cell communication and the Cell Cycle I. Cell Cycle –...
Cancer and Cell Cycle Regulation 1
Cancer, Cell communication and the Cell Cycle
I. Cell Cycle – Chapter 18
You will not be responsible for: details of S-CdK functionmechanisms of spindle assembly and anaphasespecific details of the caspase cascade & bcl-2 familytopics on extracellular signals (pp 636- 640) not covered in class
Review mitosis on your own Panel 18-1, etcRead 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 2
What are the stages of the cell-cycle?-- a review
G1
S
G2
M
G0
Table 18–1 Some Eucaryotic Cell-Cycle TimesCell type Cell cycle timeEarly frog embryo cells ~30 minutesYeast cells 1.5–3 hoursIntestinal epithelial cells ~12 hourscultured fibroblasts ~20 hoursHuman liver cells ~1 year
Cancer and Cell Cycle Regulation 3
Tumor suppressor proteins are ‘Gatekeepers’ and ‘Caretakers’ of the cell
Stop
Go
Die
Cancer and Cell Cycle Regulation 4
Mutated Tumor Suppressor Genes disable the corresponding Tumor Suppressor Proteins . . .
Cells progress toward metastasis
Cells do not die when they should
Cells divide when theyshouldn’t
Tick and Sick-6 5
Cells of cancers accumulate numerous chromosomal abnormalities
Deletions
Translocations
Inversions
Duplications
Meningioma karyotypeAneuploidy - #s 7, 9, 20
Missing homolog - #1, 17, YTranslocations - #s 2, 6, 7
Should triggerapoptosis
Tick and Sick-6 6
Some examples of inactivated Tumor Suppressor Proteins and Oncogenes
Cancer and Cell Cycle Regulation 7
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 8
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
Synchronously dividing cells
Ques 18-2Where are G1,S,G2, & M stage cells?
DAPI stained cells
Cancer and Cell Cycle Regulation 9
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 10
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 11
What do we know about MPF & cyclin?
MPF is a cyclin bound to a Cdk ‘cyclin-dependent protein kinase’
= M-Cdk
Several Cyclins and Cdks -- regulate different cell cycle events
Table 18–2 The Major Cyclins and Cdks of Vertebrates
Cyclin–Cdk Complex Cyclin Cdk partner G1-Cdk cyclin D Cdk4, Cdk6 G1/S-Cdk cyclin E Cdk2 S-Cdk cyclin A Cdk2 M-Cdk cyclin B Cdk1
Cancer and Cell Cycle Regulation 12
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 13
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) Phosphorylates H1 histone (triggering C’some condensation)
2) Disassembly of nuclear lamina3) Changes behavior of microtubules
-- phosphorylates MAPs4) etc…??
Cancer and Cell Cycle Regulation 14
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 15
How do checkpoint proteins (i.e.,TSPs) suppress celldivision?
P53, BRCA1, P21 and Rb are all TSPs -- loss of both alleles necessary
Why?P53 can also trigger apoptosis
Figures 18-14 + 18-15
Cancer and Cell Cycle Regulation 16
What are the mechanisms of apoptosis activation and cellular destruction?
Intrinsic vs extrinsic activation
Caspase family of proteases-- activation ‘cascade’
Intrinsic activation signals-- cell injury, P53 activation, etc-- lack of survival signal
Extrinsic activation signals-- cell-surface receptors (Fas/FasL)-- cellular toxins (Granzymes)
Caspase cascade
Intrinsic pathway
Question 18-10, p 635Why apoptosis rather than
necrosis?