Control of Cell Cycle

Unit 2 Part f

III

How often do cells divide and why?

• The timing and rate of cell division in different parts of the plant or animals are crucial to normal growth, development and maintenance.

• Frequency – depends on the type of cell

• human skin cells – frequently throughout life

• Liver – maintains ability to divide but only do it when required

• Nerve/Muscle – do not divide

Why the Differences?

• Regulation occurs at the molecular level.

Figure 12.1

100 µm

(a) Reproduction. An amoeba, a single-celled eukaryote, is dividing into two cells. Each new cell will be an individualorganism (LM).Figure 12.2 A

Control System

• The cell cycle control system is a cyclically operating set of molecules in the cell that both triggers and co-ordinates key events in the cell cycle.

• Internal controls which are built in but there are external adjustments that take place.

Cell Cycle Checkpoints

• A checkpoint in the cell is a critical point where stop and go-ahead signals can regulate the cycle.

• The signals report whether crucial cellular processes up to that point have been completed correctly, and so whether or not the cell cycle should proceed

• Checkpoint also register signals from outside the cell.

• http://outreach.mcb.harvard.edu/animations/checkpoints.swf

• Normal Cell Division Animation

G1 Checkpoint

• Occurs towards end of G1 phase• If go ahead is received at G1 checkpoint then the

cell cycle will most likely proceed and division will take place

• Enough cell growth needs to have occurred before the cell can enter the S phase of interphase.

• If NOT, it will exit switching into a non dividing state call the G0 phase.

• Most cells in the human body are actually in G0 phase e.g. Nerve and Muscle cells

G2 Checkpoint

• Occurs at the end of G2.

• Where DNA replication is assessed in order for the cell cycle to continue.

• Controls entry into mitosis.

• Ensures new daughter cell receives all the genetic information needed.

M Checkpoint

• Occurs during metaphase and before anaphase of mitosis

• Checks if the chromosomes have aligned to the spindle

Figure 12.14

Control system

G2 checkpoint

M checkpoint

G1 checkpoint

G1

S

G2M

G1 checkpoint

G1G1

G0

(a) If a cell receives a go-ahead signal at the G1 checkpoint, the cell continues on in the cell cycle.

(b) If a cell does not receive a go-ahead signal at the G1checkpoint, the cell

exits the cell cycle and goes into G0, anondividing state.

Figure 12.15 A, B

Where cell cycle stops until it receives the go ahead signal

Cell Cycle Regulation

• Cell cycle needs regulation to ensure events proceed in the correct order and that each event is completed before the next event starts.

• To understand this we need to examine the types of molecules that make up the cell cycle control system

• Certain molecules determine the sequence of cell cycle.

In each experiment, cultured mammalian cells at two different phases of the cell cycle were induced to fuse.

When a cell in the M phase was fused with a cell in G1, the G1 cell immediately began mitosis—a spindle formed and chromatin condensed, even though the chromosome had not been duplicated.

EXPERIMENTS

RESULTS

CONCLUSION The results of fusing cells at two different phases of the cell cycle suggest that molecules present in the cytoplasm of cells in the S or M phase control the progression of phases.

When a cell in the S phase was fused with a cell in G1, the G1 cellimmediately entered the S phase—DNA was synthesized.

S

S S M M

MG1 G1

Experiment 1 Experiment 2

Figure 12.13 A, B

Cell Cycle Clock

• Cell cycle control molecules pace the sequence of events of the cell cycle.

• Their abundance and activity can cause rhythmic fluctuations.

Cyclins and Cyclin Dependent Kinases

• Protein kinase enzymes activate or inactivate other proteins by phosphorylating them.

• Two groups of proteins, cyclins and cyclin-dependent kinases (Cdks), are responsible for promoting the cell cycle.

• Particular protein kinases give the go-ahead signals at G1 and G2 checkpoints.

• The kinases that drive the cell cycle are actually present at a constant concentration in a growing cell, but most of the time they are in an inactive form.

• To be active they must be attached to a protein called cyclin. When they are attached they are called cyclin-dependant kinases or Cdks. The activity of Cdk rises and falls with changes in the concentration of its cyclin.

Mitosis Promoting Factor (MPF)

• Is a Cdk.

• One of the first to be discovered

• Promotes entry into mitosis

• Regulatory protein involved in G2 checkpoint.

• Cyclins accumulate during G2 and associate Cdk molecules, the resulting MPF complex initiates mitosis by phosphorylating a variety of proteins

1. By the G2 checkpoint (red bar), enough cyclin is available to produce many molecules of MPF.

2. MPF promotes mitosis by phosphorylatingvarious proteins and including other enzymes.

3. One effect of MPF is the initation of a sequence of events leading to the breakdown of its own cyclin.

• The Cdk component of MPF is recycled. Its kinaseactivity will be restored by association with new cyclin that cumulates during interphase.

•

• As the cell size increases during G1 cyclinproteins accumulate and combine with kinases to form Cdk.

• At the G1 checkpoint there is another protein involved called retinoblastoma protein (Rb) which is to prevent excessive cell growth by inhibiting cell cycle progress until the cell is ready to divide.

Retinoblastoma

• Retinoblastoma restricts the cells ability to replicate DNA by preventing progression from the G1 to the S phase of the cell cycle. When the cell is ready to divide, the retinoblastoma is phosphorylated by Cdk’s where it becomes inactive and allows the cell cycle to continue.

• When the cyclins that accumulate during G2

associate with Cdk molecules, the resulting MPF complex initates mitosis, by phosphorylating a variety of proteins.

• The retinoblastoma protein undergoes cell cycle-regulated phosphorylation. In early G1 the protein is hypophosphorylated and its phosphorylation increases as cells progress through the cell cycle.

• During mitosis phosphates are removed and the cycle of phosphorylation starts over during the next G1 phase.

• During mitosis phosphates are removed and the cycle of phosphorylation starts over during the next G1 phase.

http://www.nobelprize.org/educational/medicine/2001/index.html

Play

Negative Regulators

• Negative regulator molecules (Rb, p53 and p21) act primarily at the G1 checkpoint and prevent the cell moving forward to division until damaged DNA is repaired.

p53

• Any damage to DNA by high-energy radiation or toxic chemicals triggers the expression of the p53 gene.

• Once made, the p53 functions as a transcription factor for several genes.

• It often activates a gene whose product halts the cell cycle by binding to the Cdks, allowing time for the cell to repair the DNA.

• P53 halts cell cycle and recruits enzymes to repair damaged DNA.

• If the DNA cannot be repaired, p53 triggers apoptosis to prevent duplication

• The p53 gene therefore prevents a cell from passing on mutations due to DNA damage. If mutations do accumulate and the cell survives through many divisions cancer may occur.

Abnormal Cell Division

• http://outreach.mcb.harvard.edu/animations/checkpoints.swf

• Animation on Abnormal Cell Division

Cancer Cells

25 µm

Cancer cells do not exhibitanchorage dependence or density-dependent inhibition.

Cancer cells. Cancer cells usually continue to divide well beyond a single layer, forming a clump of overlapping cells.

(b)

Figure 12.18 B

• Malignant tumors invade surrounding tissues and can metastasize

– Exporting cancer cells to other parts of the body where they may form secondary tumors

Cancer cells invade neighboring tissue.

2 A small percentage of cancer cells may survive and establish a new tumor in another part of the body.

4Cancer cells spread through lymph and blood vessels to other parts of the body.

3A tumor grows from a single cancer cell.

1

Tumor

Glandulartissue

Cancer cell

Bloodvessel

Lymphvessel

MetastaticTumor

Figure 12.19

Research

• Types of mutations asosociated with cancer.

• For example the influence of environmental factors and viruses, the conversion of proto-oncogenes into oncogenes and mutation in tumour suppressing genes.