1. AP: Cell Cycle Regulation

2. Cell Cycle 2 crucial factors for normal growth:
Timing and rate of cell division
Cell division frequency depends on cell type:
skin cells: frequently
Liver cells: can divide when needed (eg. Repair a wound)
Mature nerve cells, muscles: do not divide

3. What drives the cell cycle?
Hypotheses:
Each event in the cycle triggers the next
incorrect
Cell cycle is driven by specific molecular signals
Evidence came from experiments with mammalian cells grown in culture

4. Cell cycle is driven by specific molecular signals

5. Cell cycle control system
A cyclically operating set of molecules in the cell
Triggers and coordinates key events in the cell cycle
Regulated at certain checkpoints
Regulated by both internal and external controls

6. checkpoints Signals transmitted by signal transduction pathways
Built-in stop signals: stop cell cycle at checkpoints
Overridden by go-ahead signals
Signals report if crucial cellular processes completed correctly
Also register signals from outside the cell
3 major checkpoints: G1, G2 and M

7. G1 checkpoint Restriction point in mammalian cells Most important
if pass, usually complete whole cycle
If no go-ahead signal  G0 phase
Most human body cells in G0 phase
Can called back from G0 phase by external cues (eg. growth factors)

8. The Molecular basis for the cell cycle clock
Rhythmic fluctuations
Abundance and activity of cell cycle control molecules
Two main types of regulatory molecules (proteins):
Kinases
Cyclins

9. kinases
enzymes that phosphorylate other proteins to active/inactive them
Specific kinases give the go-ahead signals at G1 and G2 checkpoints
Constant concentration
Inactive unless attached to a cyclin
Thus known as cyclin-dependent kinases
Cdk + Cyclin  MPF

10. MPF maturation-promoting factor/M-phase promoting factor Functions:
as kinase
Initiates mitosis
Contributes to chromosome condensation and spindle formation
Activates other kinases
Phosphorylates a variety of proteins
Eg. Phosphorylates protein of the nuclear lamina
 fragmentation of nuclear envelope

11. Self-regulation of MPF
During anaphase, MPF initiates destruction of its own cyclin
Cdks persist as inactive form

12. Internal signal at checkpoints
M phase checkpoint
Kinetochores not yet attached to spindle microtubules send molecular signal
 Sister chromatids stayed together, delay anaphase
When kinetochores of all chromosomes are attached
Inactive protein holding sister chromatids
Sister chromatids separate (anaphase)
Ensures right number of chromosomes in daughter cells

13. External chemical signal
Cells in culture cannot divide if missing an essential nutrient
Eg. Growth factor
Mitogen: a growth factor protein that promotes mitosis
Eg. Platelet-derived growth factor (PDGF)
Required for division of fibroblasts
Fibroblast: a type of connective tissue cell with PDGF receptors
Binding allows cell to pass the G1 checkpoint and divide
Injury  platelets release PDGF

14. External physical signal: Density-dependent inhibition
Crowded cells stop dividing
Cultured cells form a single layer on inner surface of container
If cells are removed, cells bordering space will divide to fill in
Reasons:
Physical contact (minor)
Amount of required growth factors and nutrients available (major)

15. External physical signal: Anchorage dependence
Requires substratum
Eg. Inside of culture container or extracellular matrix of a tissue
Signaled through pathways using plasma membrane proteins and cytoskeleton

16. Cancer cells Do not respond normally to body’s control mechanisms
No density-dependent inhibition
No anchorage dependence
Divide excessively
Invade other tissues  may kill organism
Stop dividing at random points in the cycle, instead of at checkpoints
Immortal: can divide indefinitely if given continual supply of nutrients
Eg. HeLa cells: a cultured cell line from 1951, Henrietta Lacks’s tumour
Vs normal cells in culture only divide times

17. Cancer cells Hypotheses for NO density-dependent inhibition:
Do not need growth factors to grow and divide
May make a required growth factor themselves
Abnormal signal pathway to convey GF’s signal even in its absence
Abnormal cell cycle control system

18. Cancer cells - Transformation
process that converts a normal cell to a cancer cell
Escape destruction from body’s immune system
Forms tumour (a mass of abnormal cells within otherwise normal tissue)
If remain at original site
 benign tumour (no serious problem, can be completely removed by surgery)
If becomes invasive to impair functions of one/more organs
 malignant tumour (cancer)

19. Malignant tumour (cancer)
Excessive proliferation
Unusual number of chromosomes (cause or effect?)
Metabolism may be disabled
No constructive function
Abnormal changes on cells’ surfaces  lose/destroy attachment to neighboring cells and extracellular matrix
Can spread into nearby tissues
Can secrete signal molecules to cause blood vessels to grow toward the tumour

20. metastasis a few tumour cells separate from original tumour
enter blood/lymph vessels
travel to other parts of body
proliferate and form a new tumour

21. Treatments – localized tumour
high-energy radiation
Damages DNA in cancer cells
normal cells can repair damage, cancer cells cannot

22. Treatments - Metastatic tumour
chemotherapy through circulatory system
Interfere with specific steps in cell cycle
Eg. Taxol prevents microtubule depolymerisation
freezes mitotic spindle
stops actively dividing cells at metaphase
Side effects due to drug’s effect on normal cells
Nausea (intestinal cells)
hair loss (hair follicle cells)
susceptibility to infection (immune system cells)

23. Taking it further
Transformation always involves alteration of genes that affects the cell cycle control system