1. Phases of the Cell Cycle
Prophase
Metaphase
Anaphase
Telophase

2. Cell Cycle Progression:
Requirements
G2-M
Cell Division
G1-S

3. Cell Cycle Control
Requirements:
Cyclin:Cdk Complex
Activated Protein Kinase

4. Expression Levels of Cyclins Oscillate

5. Various cell cycle phase-Cdks and Cyclins

6. Cdk Activation and Inactivation
M-Cdk
CAK
(Cdk Activating
Kinase)

7. Cdks can be inhibited while in a complex with a Cyclin
Cyclin Dependent Kinase Inhibitor (CKI)

8. Control of Cyclin levels During the Cell Cycle
Consequences: Decrease M-Cyclin, inactivate M-Cdk, and
allow cytokinesis (cell division) to proceed.

9. Control of CKI (p27, p21, p16) levels During the Cell Cycle
Consequences: Decrease CKI, increase Cdk/Cyclin Activity,
and allow cell cycle progression.

10. Cell Cycle CheckpointsOn
Off
Off
Off
On/Off Switches

11. On/Off Switches On
Off On
Off
Off
Off
Off On On On On

12. Control of Chromosome Duplication
Helicases

13. Activation of M-Cdk

14. The M to G1 Transition is Regulated by Stable Inhibition of M-Cdk

15. Guanine Exchange Factor
Mechanism of MAPK (ERK) activation and cell proliferation.
(Favorable Environment)
Ras-Small GTPase
Adaptor
GDP PY YP
GTP
Guanine Exchange Factor
(GEF)
Transcription Factors
Cell Cycle Genes are turned on/off
(i.e. G1/S-Cyclins and S-Cyclins)

16. Mechanisms of ERK1/2-mediated cell growth
(Due to a Mutation in Ras/Raf)
Cell Death
Cell Cycle Progression
Cell Cycle Inhibitors
i.e. CDKI: p27

17. ERK1/2-mediated cell growth Favorable Environment
Cell Cycle Inhibitors
i.e. CKI: p27
Cell Cycle Arrest
Mechanism of
ERK1/2-mediated cell growth
Unphosphorylated
Stable FOXO3a
phosphorylated
Degraded
ERK1/2
FOXO3a
CKI (p27)
CdK/Cyclin
Favorable Environment
(Growth Factors!)

18. Regulation of Cell Death (Apoptosis)
Anti-Apoptotic
Pro-Apoptotic
Unphosphorylated
BAD and BIM
Apoptosis
Phosphorylated
P-BAD and P-BIM
Sequestered (BAD)
or Degraded (BIM)
Cell Cycle
Progression

19. Mechanism of ERK1/2-mediated cell cycle progression
Cell Death
Mechanism of ERK1/2-mediated cell cycle progression
Sequestered away from Bcl-2, Mcl-1, Bcl-XL
P-BIM is polyubiquitinylated and
degraded by the Proteasome
Favorable Environment
(Growth Factors!)

20. Review: Favorable Environments for G1 Entry
Mitogens:
Growth Factors such
EGF, insulin, HRG, etc
Receptor Tyrosine Kinase (RTK, i.e. EGFR)
Mitogen Activated Protein Kinases (MAPKs. i.e. ERK)
Transcription Factors (i.e. AP-1)
Other Transcription Factors (i.e. Myc)
Cyclins (G1 Cyclin)

21. Regulation of G1 to S Phase Transition
G1-Cyclin

22. DNA Damage and Cell Cycle Arrest in G1
UV or Chemotherapy
E3 Ligase
(gene name = WAF1)

23. CKI The Activation of p21 (CKI) by p53 results
in inactivation of G1/S-Cdk Complex.
Consequence
G1/S Cell Cycle Arrest
CKI

24. The Mechanism by which p53 Arrests Cells in G1/S Phase
DNA Damage (radiation or chemotherapy)
p53
Cell Death (Apoptosis)
Waf1 gene encodes the p21 protein (CKI) On
p21 Protein Rb
E2F
P-Rb
G1/S-Cdks
G1/S-Cyclins
DNA
DNA is not repaired
CKI

25. Cell Cycle Arrest or Apoptosis Caused by Excessive Mitogenic Stimulation