AH Biology: Unit 1

Apoptosis

What do falling leaves, the development of a mouse’s paw and a tadpole losing its tail all

have in common?

What do falling leaves, the development of a mouse’s paw and a tadpole losing its tail all

have in common?

Answer: They all depend on programmed cell death.

Apoptosis: Programmed Cell Death

A matter of life or death for cells!

(Greek for ‘falling off’)

Control of apoptosis: contents

• Purpose of apoptosis

• Comparison to necrosis

• Mechanism of apoptosis

• Initiation of apoptosis:- intracellular death signals- extracellular death signals

• Malfunction of apoptosis: causes and consequences

Why do multicellular organisms need to regulate the death of their cells?

Why do multicellular organisms need to regulate the death of their cells?

• To allow body structures to grow and develop correctly.

Why do multicellular organisms need to regulate the death of their cells?

• To remove body structures that are no longer required.

Why do multicellular organisms need to regulate the death of their cells?

• To regulate the sizes of cell populations in adult bodies cell proliferation must be balanced with cell death.

• This allows organisms to precisely control the sizes of their tissues and organs.

Death can be good for the body…

Normal tissue

Tumour

Tumour

Cell division (proliferation)

Cell death (by apoptosis)

Why do multicellular organisms need to regulate the death of their cells?

• To prevent cells from surviving in environments where they should not be present.

Why do multicellular organisms need to regulate the death of their cells?

• To kill cells that have been infected by pathogens.

• To prevent the survival of cells with damaged DNA (these have the potential to become cancerous).

• To eliminate white blood cells that would produce an immune response to the body’s own cells.

The two forms of cell death

1. Apoptosis: programmed cell death

2. Necrosis: uncontrolled cell death

Animated comparison

Apoptosis compared to necrosis: What happens to the cell when it dies?

Feature Apoptosis Necrosis

Regulated by organism Yes: involves a series of enzyme-controlled reactions

No: can occur as a result of injury

DNA broken down Yes Only after cell has lysed

Cell membrane disintegration

No Yes

Nuclear membrane broken down

Yes No

Number of cells affected May be single cells Usually sheets of cells

Energy requirement ATP dependent (active process)

Energy input not required (passive process)

Fate of dead cells Ingested by neighbouring cells or phagocytes

Ingested by phagocytes

Leakage of cell contents No Yes

End point Cell fragments into smaller bodies

Lysis of whole cell

The mechanism of apoptosis

1. Activation of procaspase proteins

Active caspase B

Active caspase A

Inactive procaspase

Prodomain

The mechanism of apoptosis

2. Caspase activation cascade

Active caspase A

Active caspase BActive caspase C

The mechanism of apoptosis

3. Caspases are proteinases: they cleave key cell proteins

Inactive DNAse

Active DNAse

Nuclear lamins

Fragmented nuclear lamins

Gelsolin Actin-digesting enzyme

Caspase activity

The mechanism of apoptosis

4. Caspase activity results in the controlled destruction of the cell

Active DNAseBreakdown of nuclear DNA

Fragmented nuclear lamins

Disassembly of nucleus

Actin-digesting enzyme Disassembly of cytoskeleton

Initiation of apoptosis: the death signal

• Adaptor proteins cause initiator procaspases to cluster together.

• Clustering induces a conformational change that activates the procaspases.

Caspase activation Caspase cascade

Intracellular death signals

• Mitochondrion-mediated pathway

1. Damaged mitochondrion

3. Caspase cascade

2. Cytochrome C protein released

Intracellular death signals

• DNA damage can trigger apoptosis via the p53 protein.

Damaged DNA

Caspase cascade

Increased concentration of p53 protein in cell

Increased transcription of genes that code for proteins that activate procaspases

Increased protein kinase activity

Extracellular death signals: survival factors

• Animal cells undergo apoptosis if they are deprived of survival factors released by other cells.

• This ensures that cells only survive in locations where they are needed, when they are needed.

• The default program for most cells is suicide!

Extracellular death signals: inhibitory signal proteins

­ Some signal proteins oppose the effects of growth factors and survival factors. They can inhibit the growth of organs by stimulating apoptosis.

­ For example, mouse limb formation (see earlier images D, E, F and G).

Extracellular death signals

• Body cells infected with certain pathogens, eg some viruses, present fragments of antigenic proteins on surface receptor proteins on their cell membranes.

Extracellular death signals

• Activated killer T lymphocytes can recognise body cells displaying antigens. The lymphocytes bind surface receptor proteins on the target cell and trigger apoptosis.

Animation

Putting it together

Initiation of apoptosis by killer T lymphocytes

Target cell

Lymphocyte

Initiation of apoptosis by killer T lymphocytes

Animation

Target cell Caspase cascade

Which cellular events could cause the control of apoptosis

to be impaired?

What could be the consequence of impaired apoptosis to:

(a) the affected cell?(b) the organism containing the affected cell?

Cancer

• The development of some forms of leukemia is promoted by the loss of control of apoptosis.

• Mutations to the DNA of B lymphocytes can cause them to produce abnormally large quantities of a protein that inhibits apoptosis.

• p53 is a cancer-critical gene.

3. Inhibition of procaspase activation

4. Cell develops resistance to apoptosis

5. Survival of B lymphocytes that would normally have died

1. Chromosome translocation

2. Over-expression of a regulatory protein

Further reading and viewing

• College of St Benedict/St John’s University website

• Protein Data Bank website (p53)

• Apoptosis animation