AH Biology: Unit 1

Control of the Cell Cycle

The cell cycle: summary

G1

G2

S

Interphase

M Cytokinesis

Mitosis

The cell cycle: summary

G1

G2

S

Interphase

M

Cytokinesis Telophase Anaphase

Prophase Metaphase

Mitosis

­ Why does the progress of a cell through the cell cycle need to be monitored and regulated?

­ What features should an effective cell cycle control system possess?

The cell cycle control system can be studied using model organisms

• Yeast: Identification of mutations that arrest the cell cycle at specific points. Affected genes are known as cell-division-cycle (cdc) genes.

The cell cycle contains control points

G1

G2

S

I

M

G1 checkpoint

(entry to S phase)

G2 checkpoint(entry to M phase)

M checkpoint(exit from M phase)

The cell cycle contains control points

G1

G2

S

I

M

G1 checkpoint

(initiation of DNA replication)

G2 checkpoint(assembly of spindle fibres)

M checkpoint(initiation of anaphase)

The control points are checkpoints for the cell cycle control system

If events have not been completed the control system receives signals and arrests the cell cycle.

G1

G2

S

IM

G1 checkpoint: Has the cell reached a sufficient size? Are environmental conditions favourable? G2 checkpoint: Has

all nuclear DNA been replicated?

M checkpoint: Are all chromsomes attached to spindle fibres?

The G1 checkpoint

• Timing: Towards the end of G1 phase.

• Controls: Entry to S phase (triggers the initiation of DNA replication).

• Assesses: Cell size and environmental conditions.

• Purpose: Ensures that sufficient cell growth has occurred and environmental conditions are favourable for proliferation.

What could happen to a yeast cell whose G1 checkpoint mechanism has

been inactivated?

Cell size

Time

With nutritional cell cycle control

Nutrient supply reduced

Without nutritional cell cycle control

In multicellular organisms the G1 checkpoint operates through intracellular and

extracellular signals

Fibroblast grown in culture with adequate nutrient supply and serum

Fibroblast grown in culture with adequate nutrient supply and plasma

Cell progresses through cycle and proliferates

Cell cycle is arrested

Serum contains a protein that can bind to cells and stimulate them to progress through the cell

cycle.

Extracellular signal molecules with this function are called mitogens.

The most important decision

• Cells may either proliferate or leave the cell cycle.

• In the absence of mitogens cells enter a non-dividing state called the G0 phase.

• Cells can become terminally differentiated and remain in G0 permanently or re-enter the cell cycle when they receive appropriate signals.

G1

G2

S

Interphase

M Cytokinesis

Mitosis

G0 Reversibilitydepends on cell type

Some types of cell can proliferate continuously

• Stem cells

• Tumour cells

Most liver cells exist in a reversible G0 phase

G1

G2

S

I M

G0

G1

G2

S

I M

G0

Normal hepatocyte: mitogenic signal absent

Cell proliferation is stimulated by damage to liver

Red blood cells, neurons and skeletal muscle cells exist in a terminally

differentiated G0 state

The G2 checkpoint

• Timing: End of G2 phase.

• Controls: Entry to M phase (triggers assembly of mitotic structures).

• Assesses: Completion of DNA replication.

• Purpose: Ensures that all DNA is replicated so that daughter cells can each receive a complete copy of the genome and function correctly.

The M checkpoint

• Timing: During metaphase.

• Controls: Exit from M phase (triggers anaphase and cytokinesis).

• Assesses: Attachment of all chromosomes to spindle fibres.

• Purpose: Ensures that each daughter cell receives the same chromosome complement as its parent when anaphase occurs.

The M checkpointAll chromosomes attached to spindle fibres

One chromosome is not attached to spindle fibres

Cell cycle progresses: cell enters anaphase

Cell cycle arrested until all chromosomes are properly attached

Checkpoints operate through negative intracellular signals

• The presence of unattached chromosomes generates signals that stop the cell from progressing to anaphase.

The molecular mechanisms of cell cycle control

The cell cycle is controlled by the activity of cyclin-dependent kinases (Cdks)

G1

G2

S

M

Cdk active

Cdk active

Cdk inactive

Cdk inactive

The cell cycle control system can be studied using model organisms

• Spisula: a mollusc used in the study of protein synthesis (eg of cyclins) in embryonic cells.

A time course of intracellular cyclin protein

Time

Relative level of cyclin protein

Mitosis Mitosis Mitosis

The activity of Cdks is regulated by cyclins

Inactive Cdk

Cyclin binding

Cdk with protein kinase activity (cyclin–cdk complex)

Different cyclins bind to Cdks at different phases of the cell cycle

- The binding of G1-cyclins allows a cell to pass through the G1 checkpoint.

- The binding of S-cyclins allows a cell to initiate DNA replication in the S phase.

- The binding of M-cyclins promotes the events of mitosis.

The activation of cyclin-Cdk complexes triggers cell cycle events

A certain level of phosphorylation of target proteins results in the cell progressing to the next stage of the cycle.

G1

G2

S

M

Mitosis triggered

DNA replication triggered

M-Cdk

S-Cdk

G1-Cdk

Active retinoblastoma protein (Rb) inhibits cell cycle progression

S G1

Retinoblastoma is targeted by G1-Cdk

Active G1-Cdk

P P

Active Rb Inactive Rb

What would be the consequence of a mutation to the gene that codes for the Rb protein?

Synthesis of S-cyclins

Active S-Cdk

DNA replication

The cell cycle has checkpoints for DNA damage

Mutagen

In which part(s) of the cell cycle would you expect these checkpoints to occur?

What should a cell with damaged DNA do?

DNA damage prior results in the activation of the protein p53

1. Damaged DNA

2. Protein kinase activity triggered

Unstable p53 Stable p53

P

Active p53 can promote the transcription of genes that induce cell cycle arrest

P

Regulatory DNA Expression of p21 gene

p21 protein

Cyclin–Cdk complex inactivatedCell arrested in G1

Active p53 can affect a cell in different ways

What would be the functional consequences of an inability to activate p53?

PStimulates DNA repair

Promotes transcription of genes that induce apoptosisPromotes

transcription of genes that induce cell cycle arrest

Ataxia telangiectasia: a genetic disease associated with an inability to activate p53

What could cause the development of telangiectases (small clusters of enlarged blood vessels)?

Cell cycle review

Interactive cell cycle animation.

Control of cell cycle game on the Nobel Prize website (simulation).

Animation of the action of the Rb and p53 proteins.