1. Regulation of Cell Division

2. Coordination of cell division
Multicellular organism coordinate cell division in diff tissues & organs
Needed for normal growth, development & maintenance
coordinate timing
coordinate rates
cell cycle not always the
same

3. Frequency of cell division
embryo
< 20 minute
skin cells
divide often in life
12-24 hours
liver cells
retain ability to divide
once every year..ish
nerve & muscle cells
do not divide
stuck in G0 G2 S G1 M
metaphase
prophase
anaphase
telophase
interphase (G1, S, G2 phases)
mitosis (M)
cytokinesis (C) C

4. Checkpoint control system
Checkpoints
Cycle controlled by STOP & GO chemical signals
signals if cellular processes completed correctly

5. Checkpoint control system
3 major checkpoints:
G1/S
DNA synthesis ready?
G2/M
DNA synthesis completed correctly?
spindle checkpoint
all chromosomes attached
to spindle?
sister chromatids able to separate?

6. G1/S checkpoint G1/S most critical “restriction point”
if “GO” signal, it divides
internal signals: cell size, nutrition
external signals: “growth factors”
No signal? exits cycle to G0 phase
non-dividing
working state

7. G0 phase G0 phase non-dividing most human cells in G0 liver cells
nerve & muscle cells

8. Activation of cell division
Knowing when to divide?
cell signals
chemical signals in cytoplasm
signals = proteins
activators
inhibitors
experimental evidence: Can you explain this?

9. “Go-ahead” signals Protein signals cause growth & division
internal
“promoting factors”
external
“growth factors”
Primary mechanism of control
phosphorylation
kinase enzymes
activates or inactivates signals
We still don’t fully understanding the regulation of the cell cycle. We only have “snapshots” of what happens in specific cases.

10. Cell cycle signals controls cyclins Cdk’s Cdk-cyclin complex proteins
inactivated Cdk
Cell cycle signals
controls
cyclins
proteins
levels cycle in the cell
Cdk’s
cyclin-dependent kinases
phosphorylates cellular proteins
activates or inactivates proteins
Cdk-cyclin complex
triggers passage through different stages of cell cycle
activated Cdk

11. Cyclins & Cdks Interaction of Cdk’s & cyclins triggers stages of cycle
There are multiple cyclins, each with a specific role. Cyclins are unstable. Some are triggered for destruction by phosphorylation. Others are inherently unstable and are synthesized discontinuously during the cell cycle.
Oscillations in the activities of cyclin-dependent kinases (CDKs) dictate orderly progression through the cell division cycle. In the simplest case of yeast, a progressive rise in the activity of a single cyclin-CDK complex can initiate DNA synthesis and then mitosis, and the subsequent fall in CDK activity resets the system for the next cell cycle.
In most organisms, however, the cell cycle machinery relies on multiple cyclin-CDKs, whose individual but coordinated activities are each thought to be responsible for just a subset of cell cycle events.

12. Spindle checkpoint G2 / M checkpoint M cytokinesis C G2 mitosis G1 S
Chromosomes metaphase plate
Replication completed
DNA good
Inactive
Active
Active
Inactive
Cdk / G2 cyclin (MPF) M
APC
cytokinesis C G2
mitosis G1 S
Cdk / G1 cyclin
Inactive
Active
MPF = Mitosis Promoting Factor
G1 / S checkpoint
Growth factors
Nutrition of cell
Size

13. External signals Growth factors coordination between cells
protein signals released by body cells that stimulate other cells to divide
density-dependent inhibition
crowded cells stop dividing
each cell binds a bit of growth factor
not enough activator left to trigger division in any one cell
anchorage dependence
to divide cells must be attached to a substrate
“touch sensor” receptors

14. Growth factor signals growth factor cell division cell surface
nuclear pore
nuclear membrane P P
cell division
cell surface
receptor
Cdk
protein kinase
cascade P
E2F P
chromosome Rb P
E2F
cytoplasm Rb
nucleus

15. Example of a Growth Factor
Platelet Derived Growth Factor (PDGF)
made by platelets
Promotes wound heal
Erythropoietin (EPO): A hormone produced by the kidney that promotes the formation of red blood cells in the bone marrow. EPO is a glycoprotein (a protein with a sugar attached to it).
The kidney cells that make EPO are specialized and are sensitive to low oxygen levels in the blood. These cells release EPO when the oxygen level is low in the kidney. EPO then stimulates the bone marrow to produce more red cells and thereby increase the oxygen-carrying capacity of the blood.
EPO is the prime regulator of red blood cell production. Its major functions are to promote the differentiation and development of red blood cells and to initiate the production of hemoglobin, the molecule within red cells that transports oxygen.
EPO has been much misused as a performance-enhancing drug (“blood doping”) in endurance athletes including some cyclists (in the Tour de France), long-distance runners, speed skaters, and Nordic (cross-country) skiers. When misused in such situations, EPO is thought to be especially dangerous (perhaps because dehydration can further increase the viscosity of the blood, increasing the risk for heart attacks and strokes. EPO has been banned by the Tour de France, the Olympics, and other sports organizations.

16. Any Questions??