1. Regulation of the Cell Cycle
SBI3UP
AP Lesson

2. Why do cells divide? Do all cells divide at the same rate? Why not?

3. Recall the Cell Cycle:

4. Two Hypotheses:
Each event in cycle triggers the next
Incorrect theory
Cell cycle is driven by specific molecular signals
Evidence came from experiments with mammalian cells grown in culture

5. The Experiment:
2 cells in different phases of cell cycle were fused to form a single cell with 2 nuclei
If one original cell was in S phase and the other in G1, the G1 nucleus entered S phase
Known due to the chemical present in cytoplasm

6. If one original cell was in M phase and the other in G1 the nucleus entered M phase
Known due to formation of spindle and condensing of chromosome
However, the chromosomes would not be duplicated

7. S and G1  S phase
M and G1  M phase

8. What if the 1st theory was correct
What if the 1st theory was correct? How would the results of the experiment differed?

9. Experiments concluded that events of are directed by a cell cycle control system
Set of molecules that trigger/coordinate cell cycle events
It operates on its own
The control system is subject to external/internal control

10. Cell Cycle Checkpoints:
Point in cell cycle where stop/go signals regulate cycle
Signal checks that important processes have been complete
E.g. cell size, DNA replication, spindle fiber attachment
Checkpoints are found in G1, G2, and M phase

12. The G1 Checkpoint:
G1 has been known as the “restriction point” in mammalian cells
If cells pass G1 checkpoint they will likely divide
If cells don’t pass G1 checkpoint they go to G0 phase  non- dividing
E.g. nerve cells, liver cells

13. What if a cell ignored the checkpoint at the G1 phase
What if a cell ignored the checkpoint at the G1 phase? What would be the consequences?

14. 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

15. Phosphorylating other proteins to activate/inactivate them
Kinases:
Phosphorylating other proteins to activate/inactivate them
Give “go ahead” at G1 and G2 checkpoints
Present in constant concentrations
Inactive unless attached to a cyclin
Thus known as cyclin-dependent kinases (Cdk)
Cdk + Cyclin  MPF
Phosphorylation is the addition of a phosphate group to a protein.

16. 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

17. 4. Cdk component of MPF is recycled
3. One indirect effect of MPF is the breakdown of its own cyclin
2. MPF promotes mitosis by phosphorylating various proteins/enzymes
1. Accumulated cyclin molecules combine with Cdk molecules to produce MPF by G2 checkpoint

18. When kinetochores of all chromosomes are attached
Internal Signals:
M phase checkpoint
Kinetochores not yet attached to spindle microtubules send molecular signal
Sister chromatids stay together, delay anaphase
When kinetochores of all chromosomes are attached
Anaphase-promoting complex (APC) becomes active
Triggers breakdown of cyclin and inactivation of proteins holding chromatids together
Ensures right number of chromosomes in daughter cells
Kinetochores are the protein on chromatids where spindle fibers attach. Located at the centromere.

19. External Signals:
1. Chemical
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

21. 2. 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
Why?
Physical contact (minor)
Amount of required growth factors and nutrients available (major)

23. 3. Anchorage Dependence
Requires substratum
Eg. Inside of culture container or extracellular matrix of a tissue
Signaled through pathways using plasma membrane proteins and cytoskeleton

24. How are cancer cells different from normal cells?

25. 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

26. Cancer cells are immortal
can divide indefinitely if given continual supply of nutrients and an adequate environment to grow
Eg. HeLa cells: a cultured cell line from 1951, Henrietta Lacks’s tumour
Vs. normal cells in culture only divide times

27. Hypotheses for NO density-dependent inhibition in cancer cells:
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

28. Transformation to Cancer Cells:
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)

29. Malignant Tumours:
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

30. 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

31. Treatment: Localized Tumour
high-energy radiation
Damages DNA in cancer cells
normal cells can repair damage, cancer cells cannot

32. Treatment: 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)

33. Things to Know:
Stages of the cell cycle
Cell cycle checkpoints
Molecular basis for cell cycle clock
Internal/external signals
Cancer cells: development, types of tumours, treatments