Cell Cycle

Chow et al., Nature 2009

Yudy Tjahjono, M.Sc. Biol.

 PART I
• Mitosis phase – Overview
• Control of Centriole, Microtubule, and Kinetochore
• Check points and CDK –Overview
• CDK inhibition and Activation
• Major Cell Cycle regulatory proteins
• Regulation of cell cycle by APC/C
 4 phases of the cell cycle
(< 1 hour)

(10-12 hours)

G0 Phase
 OVERVIEW MITOTIC PHASE

Prophase
Metaphase
Interphase

Anaphase
Cytokinesis

Telophase
Centriole
Microtubules
 Microtubule-dependent motor proteins
govern spindle assembly and function
• Kinesin-related prot : move toward the plus
end of microtubules
• Dynein : move toward the minus end of
microtubules
The Kinetochore
The Kinetochore
Kinetochore attachment
 Cohesins
help hold sister chromatids together
 Bi-orientation is achieved by trial and error
• Incorrect attachment are
highly unstable while correct
attachments are locked in
place (stable)
• when a sister chromatid pair is
properly bi-oriented on the
spindle, the 2 kinetochores are
pulled in opposite directions
by strong poleward forces
Checkpoints
 (3)
(2)

(1) / restriction point (late G1)

 Cyclin-Dependent Protein kinases
(Cdks)
• Cdk activity at the G2/M checkpoint :
phosphorylation of protein that control
– chromosome condensation
– Nuclear envelope breakdown
– Spindle assembly
– Other events that occur at the onset of mitosis
• Cdk + cyclin → protein kinase activity
• Cyclin-cdk complexes → triggers cell-cycle
events
Different Cycline in Cell Cycle

Start
checkpoints
Cyclin Concentration
during cell cycle
Different Cycline in Cell Cycle
Major Cyclin and Cdks
M-Cdk and S-Cdk
 CDK have
limited halflife

• Example: S-Cdk
(appr. 12 h)
The structural basis of CDK activation
Double phosporylation of CD by Wee1 kinase -
could induce inactivation

• Phosphorylation by Wee1 inhibits Cdk activity,

while dephosphorylation of these sites by a
phosphatase (Cdc25) increases Cdk activity
 CDK-Inhibition with p27 (Cyclin Kinase
Inhibitor Complexes) help govern the activites
of G1/S and S-Cdks in cell cycle

Tumorsupressor p27 Inhibit ATP-binding Site

A cascade of CDK-“Auto“activation

MPF= CDK
Major Cell-Cycle Regulatory Proteins
The cell cycle control system depends on cyclical
proteolysis
APC/C
• Progression through the metaphase-to-anaphase-
transition is triggered by protein destruction,
leading to the final stages of cell division
• Key regulator : anaphase-promoting complex/
Cyclosome (APC/C)
• APC/C catalyzes the ubiquitylation & destruction of
2 major prot:
– Securin (cleavage cohesin complexes)
– S- and M-cyclins
The cell cycle control system depends on cyclical
proteolysis
APC/C

• APC/C remains active in G1, a stable period of the Cdk

inactivity
• When G1/S-Cdks are activated in late G1, the APC/C is turned
off, allowing cyclin accumulation to start the next cell cycle
Ubiquitin and Polyubiquitin

Polyubiquitin is
recognized by 26S-
Proteasome

Leads to Protein
degradation
Control of proteolysis by APC
(Anaphase Promoting Complexes)
 END PART I
CONTINUE TO PART II
 PART II
• Control of cell cycle by SCF
• M-Cdk Activation
• Control of chromosome duplication by Pre-RC and ORC
complexes.
• Regulation of contractile Ring
• Signal transduction cascade: Control of cell division and cell
growth.
• Regulation of DNA-Damage, example: p53.