The document provides an overview of the cell cycle, including its phases (M, G1, S, G2, G0), historical perspectives on its discovery, and key mechanisms regulating progression through the cycle. Regulation involves cyclins and cyclin-dependent kinases (CDKs), restriction points, the tumor suppressor protein p53, and CDK inhibitors like p21 and p16. Precise control of the cell cycle through these mechanisms ensures genetic information is accurately replicated and transmitted between daughter cells.

1. JG NEL
DEPT OF HAEMATOLOGY AND CELL BIOLOGY
UFS
SEPTEMBER 2008
The Cell Cycle, basic concepts

2. Lecture outline
Historical perspective
Phases of the cell cycle
Regulation of the cycle
The importance of the cycle

3. Introduction
The cell is the basic structural and functional unit of
all living organisms.
Understanding how the cell cycle operates, and is
controlled, is therefore an important problem in
biology with implications for medicine

4. The cell cycle
Universal process by which cells reproduce
Underlies the growth and development of all living
organisms –central to their heredity and evolution
Results in
 Duplication
 Transmission of genetic information
The precision with which the cell cycle is executed
ensures survival of all living organisms

5. Historical perspective
What we know today is the result of work done over
the past +/- 150 years
Nägeli(1844)+Remak(1852) -described the division
of plant and animal cells
Study of the cell cycle -began with the discovery of
cell division

6. Phases of the cell cycle

7. Phases of the cell Cycle
M phase
 Karyokinesis
 Cell’s chromosomes divided between two daughter cells
 Cytokinesis
 Cytoplasm divides –forming distinct cells
G1 phase
 Between M phase and the beginning of DNA synthesis
 Cellular biosynthetic activities resume at a high rate
 Marked by the synthesis of various enzymes required in S
phase

8. Phases of the cell Cycle
S phase
 Starts when DNA synthesis commences
 Complete when all the chromosomes have been replicated
 Rates of RNA transcription and prot synth low during this
phase -with the exception of histone production

9. Phases of the cell Cycle
G2
 Lasts until the cell enters mitosis
 Significant protein synthesis occurs –mainly involving the
production of microtubules
 Inhibition of prot synth prevents cell from entering mitosis
G0
 Quiescent and senescent cells

11. Cell cycle regulation:
 Ensures the orderly progression of events so that the
nuclear cycle is coordinated with cell growth and
physical separation.
Replication must occur once per cell cycle and
precede chromosome segregation; segregation must
be complete before cytokinesis.

12. Regulation of the cell cycle

13. 2001 Nobel prize in Physiology or Medicine

14. 2001 Nobel prize in Physiology or Medicine
Leland Hartwell
 60s
 Budding yeasts, identified specific mutants that blocked specific
stages of the cell cycle
 Cell division cycle genes
 “start” gene in yeasts –CDC28
 Checkpoints
Paul Nurse
 70s
 Isolated fission yeast mutants that could speed up the cell cycle
 CDK- cdc2, CDK-1
 1987 discovers the human “start” gene
Tim Hunt
 Discovered “cyclins”

15. Regulation of the cell cycle
Crucial to the cell
Involves the detection and repair of genetic damage
Provision of various checks to prevent uncontrolled
cell division
Molecular events that control cell cycle –ordered and
directional

16. Regulation of the cell cycle
Role players:
Cyclins + Cyclin-dependent kinases
Restriction points
P53
CDK inhibitors

17. Regulation of the cell cycle:CDKs

18. CDK-2

19. Regulation of the cell cycle:CDKs
Exert their effects on cell-cycle events by
phosphorylating a large number of proteins in the
cell
Two lobed structure
Structure modified so that the active site of the CDK
is blocked in the absence of cyclin

20. Regulation of the cell cycle: Cyclins and CDKs
Cyclins -regulatory subunits
CDKs -catalytic subunits
Cyclins have no catalytic activity on their own
Cyclins with their bound and activated CDK
functions during distinct stages of the cell cycle
Activated heterodimer

21. Regulation of the cell cycle:Cyclins
Periodicity of Cyclins
 ensure well-delineated transitions between cell cycle stages
Degradation
 by ubiquination and proteasomal degradation
 Details of conjugation to ubiquitins differ
 G1 cyclins -by SCF complex
 Mitotic cyclins -by APC

22. Regulation of the cell cycle: Restriction points

23. Regulation of the cell cycle: Restriction points
Cell cycle proceeds by a defined sequence of events
 Later events depend on completion of earlier events
Regulation necessary to ensure complete and
accurate replication of genome
Checkpoints set at various stages during the cell
cycle
 Latter 1/3 of G1
 In S phase
 G2/M
 Spindle checkpoint

24. Regulation of the cell cycle: Restriction points
Checkpoints prevent cell cycle progression
-allowing :
 Verification of necesary phase processes
 Repair of DNA damage

25. The location of checkpoints in the cell cycle

26. P53 protein

27. Regulation of the cell cycle: P53
Monitors the integrity of the genome
In the presence of genomic damage –interrupts
cycling to allow time for genomic repair
Levels in normal dividing cells – low/undetectable
Negatively regulated by MDM2

28. Regulation of the cell cycle: P53
MDM2
Negatively regulates p53
 Functions at two sites
 Level of gene –down regulates p53 transcription
 Binds to P53 protein –inhibiting activity, mediating export from
the nucleus, ubiquination and proteasomal degradation

29. Regulation of the cell cycle: P53
In presence of DNA damage
 P53 binds to sequence specific DNA site –inducing increased P53
protein synthesis
 Phosphorylation of p53
 Activates the protein
 Renders the protein resistant to binding and inactivation by MDM2 –
resulting in doubling of the half life of P53 and increasing activity of the
protein
Mechanism of P53 action
Interrupts cell cycle by inhibition of Rb phosphorylation
If damage too extensive for repair induces the expression of
Bax

30. Regulation of the cell cycle: P53
Interrupts cell cycle by
 Transcriptional upregulation of P21, preventing
phosphorylation of Rb by active inhibitiob of CDK 4,6,2

31. Regulation of the cell cycle: P53

32. The Rb protein

33. Regulation of the cell cycle: Rb proteins
Pocket proteins
Sequester E2F transcription proteins
Release of E2F dependant upon the phosphorylation
state of Rb protein
 Unphosphorylated/hypophosphorylated tightly binds E2F
 Phosphorylation
 By CDK4/6
 E2F dissiociates from Rb –free to transcribe responder
genes
 Cyclin E –required for progression through restriction point

34. Regulation of the cell cycle: Rb proteins
Hypophosphorylated Rb guards restriction point –
preventing cell cycle progression

35. Regulation of the cell cycle: CDK inhibitors
Two families involved in cell cycle regulation
 Cip/Kip
 P27 +p21
 Functions at several sites in the cell cycle
 Targets –CDK 4,6,2
 INK4a
 P16INK4a
 Inhibits CDK4/6
 P19ARF
 Binds to MDM2 and blocks P53 degradation
Actions of CKI inhibits Rb phosphorylation and
subsequently keeps the cell in G1

36. The cell cycle

37. The importance of the cell cycle
Dynamic field
Study of the cell cycle is providing insights into
physiology and pathophysiology
After 150 years of study , there is still a lot of things
to learn, understand and prove.