1. Cell Cycle Checkpoint

2. The cell cycle: cells duplicate their contents and divide

3. The cell cycle may be divided into 4 phases

4. The cell cycle triggers essential processes (DNA replication, mitosis)

5. Cell Cycle Checkpoints

6. Progression of the cell cycle is regulated by feedback from intracellular events

7. Major Checkpoint Monitoring Molecules
Cyclins
Cyclin Dependent Kinases (CDKs)
p53 - DNA damage
RB - Retinoblastoma
APC - Anaphase Promotin Complex

8. Cyclin-dependent protein kinases drive progression through the cell cycle
Cyclin-dependent kinases (Cdks) are inactive unless bound to cyclins
Active complex phosphorylates downstream targets
Cyclin helps to direct Cdks to the target proteins

9. Cellular levels of (mitotic) M-cyclin rises and falls during the cell cycle
M-cyclin levels are low during interphase but gradually increases to a peak level during mitosis
M-cdk activity is, likewise, low in interphase but increases in mitosis

10. The abundance of cyclins (and the activity of Cdks) is regulated by protein degradation
M-cyclin becomes covalently modified by addition of multiple copies of ubiquitin at the end of mitosis
Ubiqutination is mediated by the anaphase promoting complex (APC)
Ubiquitination marks cyclins for destruction by large proteolytic machines called proteasome

11. Cdks are also regulated by cycles of phosphorylation and dephosphorylation

12. Cdk activates itself indirectly via a positive feedback loop

13. Distinct cyclins partner with distinct Cdks to trigger different events of the cell cycle

14. S-Cdk triggers DNA replication - its destruction ensures this happens once per cell cycle

15. Checkpoints ensure the cell cycle proceeds without errors

16. Checkpoint: DNA damage arrests the cell cycle in G1

17. Checkpoint: spindle assembly
Mitosis must not complete unless all the chromosomes are attached to the mitotic spindle
Mitotic checkpoint delays metaphase to anaphase transition until all chromosomes are attached
Prolonged activation of the checkpoint -->cell death
Mechanism of many anti-cancer drugs

18. Cells can withdraw from the cell cycle and dismantle the regulatory machinery
G0 is a quiescent state
Cdks and cyclins disappear
Some cells enter G0 temporarily and divide infrequenty (I.e. hepatocytes)
Other differentiated cell types (neurons) spend their life in G0

19. p53 Anti-tumorigenic
p53 suppresses cell replication and growth when there is DNA damage.
Impact of less that diploid complement of p53.

20. p53 Activity

21. Outcome of p53 Activation
Halts cell cycle until repair is completed.
Launches cell into apoptosis (programmed cell death).

22. Loss of RB Enables continuous DNA synthesis
Defects in p16, cyclin D, Cdk4 have same result
Found in melanoma and liposarcoma

23. Anaphase Promoting Complex (APC)

24. Checkpoint Failure

25. Cancer Normal cell division: Controlled by cell cycle checkpoints
CHECKPOINTS – critical control points that determine if a cell will move to the next portion of the cell cycle.
Cancerous cell division:
Ignores the cell cycle checkpoints
Caused by DNA mutations
Cells grow and divide out of control
Cancerous cells do not perform designated purpose.
Crowd out normal cells that do perform designated purpose.

26. Cell Cycle Checkpoints
G1/S
Monitors cell size and for DNA damage
G2/M
Replication complete, DNA damage? M
Spindle fibers connected, etc.? G0
Does body require more of my type of cell?

27. Control of cell division continued: Density Dependent Inhibition: Normal cells cease dividing once critical cell density is reached. Cancer cells do not possess this trait.

28. Cancer is a disease of the cell cycle
Cancer is a disease of the cell cycle. Some of the body’s cells divide uncontrollably and tumors form.
Tumors in Liver
Tumor in Colon

29. While normal cells will stop dividing if there is a mutation in the DNA, cancer cells will continue to divide with mutation.

30. Due to DNA mutations, cancer cells ignore the chemical signals that start and stop the cell cycle. They don’t communicate with neighboring cells and continue to grow and form tumors.