Download PG1005 Lecture 16 The Cell Cycle

PG1005
Lecture 16
The Cell Cycle
Dr. Neil Docherty
My Teaching Objectives
•  To outline the basis of the division of the cell life cycle
into 4 principal phases.
•  To introduce the concept of molecular control of cell
cycle progression.
•  To highlight the importance of cell cycle check points
in avoiding the survival of mutated cells
Rudolf Virchow (1821-1902)
•  Omnis cellula e cellula
All cells from cells (by division)
The theory followed acceptance by Virchow of the work of Robert
Remak (1815-1865) and Albert Kölliker (1817-1905).
Cell Theory
• All organisms are made up of one or more cells."
• Cells are the fundamental functional and structural unit of life."
• All cells come from pre-existing cells by division."
The Cell Life Cycle
•  The cellular growth (G) phase and the cycle of
duplication (D) of heritable material followed by
fission (F)
=The Cell Cycle (GDF)
4 major phases
G1
S
INTERPHASE
G2
M
Cell Cycle Frequency Varies With Maturation
Cell Cycle Duration Can Vary With Cell Type
•  Embryonic cells-30 minutes
•  Intestinal epithelium-12 hours
•  Cultured Fibroblasts-20 hours
Cell Cycle Control
• 
During cell replication two main systems are
operative
1)  Duplicatory machinery
Control check-Are conditions favourable for
replication, is it required?
PHASE G1 CHECKPOINT
2) Segregatory machinery
Has DNA replication been completed, has it
been completed with high fidelity?
PHASE G2 CHECKPOINT
Phosphoryl Transfer Enzymes
(Kinases) and Adaptor Molecules
Control Cell Cycle Progression
Activating
Adaptor
Activated
Kinase
KINASE
Primary
Activating
Phosphrylation
KINASE
Phosphorylative
activation of cell
cycle stage specific
substrates
e.g. enzymes
Cyclical Activation of Protein Kinases
and Cell Cycle Progression
•  Certain protein kinases (Cdks) acts as specific ON/OFF
switches for the major stages of the cell cycle
•  Kinase phosphorylation activity is cyclically varied during the
cell cycle by;
-1) Changes in expression
-2) Through binding of modulatory cyclin proteins or cdkinhibitors
-3) Via fine tuning through specific phosphorylation snd
dephosphorylation events
-4) The cyclical degradation of cyclin molecules
General Summary
Note that slow time dependent
build up of specific cyclins
then their rapid degradation
coincides with phase transitions.
N.B Not all complexes shown
for clarity-See next slide
Major Cyclin and Cdks
Complex
Cyclin
Cdk
G1-Cdk
G1/S-Cdk
S-Cdk
M-Cdk
D
E
A
B
4 and 6
2
2
1
Some Cdk-Activities
•  1. M-Cdk
Promotes chromosome condensation, nuclear
envelope destruction, mitotic spindle formation
•  2. S-Cdk
Activation and deactivation of protein complex formation
at sites at which DNA replication will originate
Inhibitory Adaptor Molecules Put the
Brakes on Cell Cycle Progression
Activating
Adaptor
Inhibited
Kinase
KINASE
Primary
Activating
Phosphrylation
KINASE
Inhibitory protein blocks
ATP binding
Blockade of phosphoryl
transferase (kinase)
activity
Cdk-Inhibitors During G1
•  After mitosis, levels of all cyclins are relatively low
•  The activity of S phase transition cyclin-Cdk
complexes is blocked by the accumulation of
inhibitors e.g (p21)
DNA Damage Response
•  Prior to S phase, stimuli increasing DNA damage
(e.g. UV light) cause activation of regulatory p53
protein.
p53 (active)
to the nucleus
Binding to regulatory region
of p21 gene
Transcription/translation
p21 protein
Repair
G1/S block
Apoptosis
Your Learning Objectives
Your learning from today should focus on being able to;
•  Define what is meant by the term cell cycle
•  Pinpoint the key stages and checkpoints of the cell
cycle
•  Explain how temporal changes in cyclin and CDK-I
inhibitor expression drive and inhibit the cell cycle
respectively
•  Describe the role of p53 in cell cycle control and
hypothesise as to how p53 mutation might play a role
in cancer