1. The Biology of Cancer Chapter 8: pRb and Control of the
Robert A. Weinberg
The Biology of Cancer
First Edition
Chapter 8:
pRb and Control of the
Cell Cycle Clock
Copyright © Garland Science 2007

2. Cell cycle clock is the master governor to decide proliferation or not
Figure 8.1 The Biology of Cancer (© Garland Science 2007)

3. Chromosomal instability (genomic instability) is one of hallmark of cancers
Figure 8.5a The Biology of Cancer (© Garland Science 2007)

4. Cells make decision about growth and quiescence during a specific period in the G1 stage
Figure 8.6 The Biology of Cancer (© Garland Science 2007)

5. The Cell cycle system, three major euk systems;
in yeast, frog, mammalian cells
Yeast; Fission ( S. pombe) and budding yeast ( S. cerevisiae)
- genetically useful; genetic manipulation
Haploid state
Cdc genes; cell-division cycle genes; ts mutant (permissive or restrictive condition
*No nuclear envelop breakage during mitosis
* budding yeast; no clear G2 phase

6. Isolation of wild-type cell-division cycle (CDC) genes from S
Isolation of wild-type cell-division cycle (CDC) genes from S. cerevisiae carrying temperature-sensitive mutations in these genes
Figure 13-4

7. Two classes of mutations in S
Two classes of mutations in S. pombe produce either elongated or very small cells
S. pombe Cdc2-Cdc13 heterodimer is equivalent to Xenopus MPF
(Cdc2 is cdk, Cdc13 is cyclin B)
Figure 13-11

8. MPF promotes maturation of Xenopus laevis oocytes
Figure 13-5

9. MPF promotes mitosis in somatic cells
Figure 13-6

10. Cell cycle-dependent fluctuations in the cyclin B levels
Cyclin B levels and MPF activity change together in cycling Xenopus egg extracts,
MPF is a dimer of a mitotic cyclin and cyclin-dependent kinase (cdk)
Figure 8.9 The Biology of Cancer (© Garland Science 2007)

11. Ossilation of cyclin levels during the cell cycle
Figure The Biology of Cancer (© Garland Science 2007)

12. Cyclins and Cdk constitute the core components of the cell cycle clock
Figure 8.7 The Biology of Cancer (© Garland Science 2007)

13. Components of the cell cycle control system
*The control of cell cycle regulation; a clock or timer; specific time
-correct order-once per cycle -binary switch on/off system
-adaptability; specific cell types or environmental
Checkpoint control; delay the cell cycle progression or arrest the cell cycle
in response to signals
-send a negative signal rather than removal of positive signal
-provide time for DNA repair or prevent the disaster

14. -Cyclin-dependent kinase (Cdks)
The cell cycle regulation are based on cyclically activated protein kinase;
Multiple cdks and cyclins regulate passage of mammalian cells through the cell cycle
-Cyclin-dependent kinase (Cdks)
-cdk regulators; *different cyclins,
*level of cyclins (transcriptionally or proteolysis),
* inhibitors (p21, 27, p16, p57 etc)
* phosphorylation or dephosphorylation (Cdc25, kinase)

15. Cdk activity are regulated by inhibitory phosphorylation and by CIPs

16. The cell cycle control system depends cyclical proteolysis; SCF, APC

17. Mitogenic signaling increase the level of cylin D
Figure 8.11b The Biology of Cancer (© Garland Science 2007)

18. Control of cyclin levels during the cell cycle and Cdk are also regulated by CdkIs
Figure The Biology of Cancer (© Garland Science 2007)

19. Control of cell cycle progression by various mitogenic signals
Inhibitory signal
TGF-beta induce the p15 CDKI
Stimulatory signal
Figure 8.14a The Biology of Cancer (© Garland Science 2007)

20. Suppression of p27 function by Akt/PKB in human breast cancer
Nuclear P27
Figure 8.16a The Biology of Cancer (© Garland Science 2007)

21. Interaction of CDK Is with Cylin-Cdks;
P27,p21 differentially affect the Cdks activity
p21, p27 stimulate Cdk4/6 at early G1, but inhibit Cdk2 from late G1-to M

22. The level of p27 is elevated in the post-mitotic cells or differentiated cells
Brdu
p27
Non-dividing granule cells of the cerebellum
Figure 8.18a The Biology of Cancer (© Garland Science 2007)

23. Cell cycle phosphorylation of Rb; Rb is the determinant of R point
(Active Rb)
(Inactive Rb)
Figure The Biology of Cancer (© Garland Science 2007)

24. Rb bind to and inhibit E2F TFs
Figure 8.23a The Biology of Cancer (© Garland Science 2007)

25. E2F TFs function as activator or repressor
Figure 8.23d The Biology of Cancer (© Garland Science 2007)

26. Structure of Rb and E2F
Figure 8.23b The Biology of Cancer (© Garland Science 2007)

27. Modification of chromatin by Rb
Figure 8.24a The Biology of Cancer (© Garland Science 2007)

28. Positive feedback loops and the irreversible of cell cycle progression
Cdk2 Rb
E2F
E-Cdk2
p27
Figure 8.25a The Biology of Cancer (© Garland Science 2007)

29. Counterbalancing the level of Cyclin D by several mitogenic signaling
G1-S progression
Figure The Biology of Cancer (© Garland Science 2007)

30. Myc : bHLH TF, contributes to the cell differentiation and cell cycle progression
Figure The Biology of Cancer (© Garland Science 2007)

31. Oncogenic activity of Myc overexpression
Many Myc-binding sites of targets
Figure The Biology of Cancer (© Garland Science 2007)

32. Table 8.2 The Biology of Cancer (© Garland Science 2007)

33. How TGF-beta blocks the cell cycle progression
Figure The Biology of Cancer (© Garland Science 2007)

34. Viral oncoprotein inhibit the Rb by direct binding;
E1A, T-Ag are sequestering and inactivating Rb
E7 tags Rb for its ubiquitination and destruction
Figure The Biology of Cancer (© Garland Science 2007)

35. Rb also control the differentiation
Myoblasts only differentiate after proliferation stops.
When growth factors are present, MyoD & Myf-5 are expressed and the myoblasts proliferate & do not differentiate.
Removal of growth factors causes myoblasts to withdraw from the cell cycle; fusion and differentiation follow.
The retinoblastoma protein (Rb) can block cell growth and is inactivated by phosphorylation in proliferating cells.
Dephosphorylation of Rb & blockage of cell cycle is a "differentiation decision".
Cdk phosphorylate MyoD and promotes its destruction
Id binds to and sequest Rb and promote cell cycle progression, If Id is overexoressed ? What happen?

36. Table 8.3 The Biology of Cancer (© Garland Science 2007)

37. Table 8.4 The Biology of Cancer (© Garland Science 2007)

38. Figure 8.35 The Biology of Cancer (© Garland Science 2007)

39. Amplification of cyclin D in cancer cells
Figure The Biology of Cancer (© Garland Science 2007)

40. Suppression of p27,free Cyclin E, Rb by Skp2
Figure 8.37a The Biology of Cancer (© Garland Science 2007)

41. Figure 8.37d The Biology of Cancer (© Garland Science 2007)

42. Figure 8.38 The Biology of Cancer (© Garland Science 2007)