1. Cancer and Cell Cycle Regulation
The Cell Cycle and Cancer – 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 ) 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
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. Cancer and Cell Cycle Regulation
The life and death of cells
Why do cells eventually die?
-- infection
-- genetic mutation
-- potentially harmful
-- reach replicative limit
How do cells die?
 Apoptosis vs Necrosis
Apoptosis
Cancer and Cell Cycle Regulation

3. Table 18–1 Some Eucaryotic Cell-Cycle Times
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 –3 hours
Intestinal epithelial cells ~12 hours
cultured fibroblasts ~20 hours
Human liver cells ~1 year
Cancer and Cell Cycle Regulation

4. Cancer and Cell Cycle Regulation
Some “oncology” terminology
Benign tumor
Malignant tumor
Metastasis
Primary vs secondary tumor
Cancer
Metastasis requires many cellular changes and is also an evolutionary process
Metastasis
Cancer and Cell Cycle Regulation

5. Cancer and Cell Cycle Regulation
Mutations that alter 3 key cell properties and “set the stage” for metastasis
 Mutations that disable DNA error detection & apoptosis
 disabling of “Tumor suppressor proteins”
 Mutations that trigger cell proliferation
 activation of “Oncogenes”
-- will discuss with Cell Communication
 Mutations that confer immortality
 activation of “Telomerase”
-- will discuss with DNA & Chromosame structure
Cancer and Cell Cycle Regulation

6. Cancer and Cell Cycle Regulation
Tumor suppressor proteins are ‘Gatekeepers’ and ‘Caretakers’
of the cell
Stop Go
Die
Cancer and Cell Cycle Regulation

7. Cancer and Cell Cycle Regulation
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

8. Cancer and Cell Cycle Regulation
Cells of cancers accumulate numerous chromosomal abnormalities
Deletions
Translocations
Inversions
Duplications
Meningioma karyotype
Aneuploidy - #s 7, 9, 20
Missing homolog - #1, 17, Y
Translocations - #s 2, 6, 7
Should trigger
apoptosis
Cancer and Cell Cycle Regulation

9. Cancer and Cell Cycle Regulation
Some examples of inactivated Tumor Suppressor Proteins
Cancer and Cell Cycle Regulation

10. Cancer and Cell Cycle Regulation
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

11. Cancer and Cell Cycle Regulation
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
DAPI stained cells
Ques 18-2
Where are G1,S,G2, & M stage cells?
Cancer and Cell Cycle Regulation

12. Cancer and Cell Cycle Regulation
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

13. Cancer and Cell Cycle Regulation
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

14. Table 18–2 The Major Cyclins and Cdks
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

15. Cancer and Cell Cycle Regulation
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

16. Cancer and Cell Cycle Regulation
How do cyclin-cdk’s trigger cellular events?
S-Cdk triggers DNA replication
-- activates replication origins
-- blocks reactivation
What does activated M-CDK do?
Phosphorylates H1 histone
(triggering C’some condensation)
Disassembly of nuclear lamina
Changes behavior of microtubules
-- phosphorylates MAPs
etc…??
Cancer and Cell Cycle Regulation

17. Cancer and Cell Cycle Regulation
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

18. Cancer and Cell Cycle Regulation
Figures
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

19. Why apoptosis rather than necrosis?
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 635
Why apoptosis rather than necrosis?
Cancer and Cell Cycle Regulation