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B io Factsheet
Apoptosis
cell death by suicide, following a well-defined sequence of events built in to the cell a bubble-like structure on the cell surface, containing the remains of brokendown organelles a condition resulting from a loss of control of orderly cell division from outside : A process or structure occurring outside the cell from within : A process or structure occurring inside the cell

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Definitions
AIDS Apoptosis Bleb Cancer Extrinsic Intrinsic PCD acquired immune deficiency syndrome: A set of conditions in which the affected individual suffers opportunistic infections as a result of a depleted immune response

programmed cell death: Another name for apoptosis, emphasising that the sequence of events leading to cell suicide is built in to the cells genetic programme.

Phagocyte a white blood cell which may remove target materials by ingestion within temporary vacuoles; the formation of vacuoles in this way is phagocytosis. Receptor a molecule, often on a cell surface, able to recognise and bind to a complementary molecule. This complementary molecule may then act as a signal for an intracellular process.

Introduction
Cells do not live forever eventually each one of them dies. Cells may be made to commit suicide this is known as apoptosis or programmed cell death. Most cells undergo about 50 mitotic divisions (known as the Hayflick constant) before apoptosis. Cells which die by committing suicide do so in a well-organised manner (Fig.1): They shrink The DNA and protein in the nucleus is degraded (broken down) The mitochondria are degraded Blebs develop on the cell surface The blebs are engulfed by phagocytes The phagocytes release signals to inhibit inflammation

Fig 1 : Simple outline of apoptosis

1. Cell 'programmed' for apoptosis Nucleus Nucleus condensing 4. Nucleus fragments. 'Blebs' collected by phagocyte if phagocyte recognises cell for apoptosis Nucleus fragmenting

2. 'Signal' received Blebs Apoptotic body 3. Nucleus condenses and cell shrinks Phagocyte (i.e. macrophages) engulfs apoptotic bodies

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Why do cells commit suicide?
There are two reasons for this. It may be part of the bodys defences against pathogens or dangerous, damaged cells. It may be part of the normal developmental process for the organism.

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Fig 2 : Reasons for apoptosis

Threats to an organism
Infected cells
Cytotoxic T-lymphocytes (white blood cells involved in defence against disease) kill virusinfected cells by making them undergo apoptosis. Some infecting viruses may use their own protection system to prevent this happening! One of the HPV (Human Papilloma Viruses) implicated in causing cervical cancer does this by producing a protein that binds to and inhibits the p53 promoter of apoptosis.

Development of an organism
Synapse formation
During development of the nervous system apoptosis removes surplus cells so that synaptic connections can be made correctly between the appropriate cells needed in a particular nerve pathway.

Autoimmunity
Cell-mediated immune responses become less extensive as the challenge to the immune system is removed. There is a danger that the active immune cells could attack the body of the host organism, so cytotoxic T-lymphocytes set off the process of apoptosis in each other (and even in themselves!). If this process does not work effectively, the immune cells may cause autoimmune diseases, such as rheumatoid arthritis, in which body tissues can be severely damaged. This autoimmune response can be fatal.

Trimming and shaping

The formation of fingers and toes on hands and feet needs the surplus tissue between them to be removed by apoptosis.

Damage to DNA
Damage to the DNA in a cell may make that cell become cancerous, or it may affect its normal pathway of development and cause birth defects. Cells with DNA damage produce large quantities of a protein, p53, which acts as a powerful inducer of apoptosis. It is interesting that many cancerous cells have mutations in the gene producing this compound, and so cannot be made to commit suicide.

During menstruation
The endometrium (the inner lining of the uterus) is shed at the beginning of the menstrual cycle as apoptosis removes cells which hold the lining in place.

During metamorphosis
The reabsorption of the tail of a tadpole as it develops into a frog depends on apoptosis as the cells of the tail must be broken down before their components can be reabsorbed.

Cancer cells
Some forms of radio and chemotherapy set off apoptosis in cancer cells, so that the cancer cells destroy themselves and the threat to the whole organism is overcome. Some very severe and aggressive forms of cancer can prevent this happening. For example, melanoma (the most dangerous form of skin cancer) cells avoid apoptosis by inhibiting the formation of one of the proteins that starts the process of breaking down cell proteins. Some lung cancer cells prevent lymphocytes from recognising dangerous dividing cells by producing a decoy molecule on their surface so that the lymphocyte cannot bind and begin apoptosis.

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Control of Apoptosis
Apoptosis is controlled by a wide range of signals, some of which come from inside the cell (intrinsic factors) and some of which come from outside the cell (extrinsic factors). Whether or not a cell commits suicide depends on a balance between two sets of signals: positive signals (such as growth factor for neurones and interleukin for mitosis of lymphocytes) which are needed for the cell to continue to survive, and negative signals (such as high levels of oxidants (e.g. peroxide ions), cytokines, nitric oxide, harmful radiation, accumulation of incorrectly-shaped proteins and death activators that bind to specific receptors on the cell surface) which signal the start of apoptosis.

Apoptosis and AIDS

During AIDS the numbers of CD4 T cells in the affected individual fall dramatically, and this individual cannot then mount an effective immune response. CD4 T cells are infected by the HIV (Human Immunodeficiency Virus), but it isnt these particles that kill off the CD4 cells. It seems that these cells are killed by apoptosis because they produce too much of a receptor (called FAS) which can bind to a death activator, causing the cells to commit suicide.

Practice Questions
1. Why is apoptosis important to living organisms? (8 marks) 2. Complete the following account of apoptosis by filling in the gaps. Apoptosis is also known as ..........................................................., because the ability to commit suicide appears to be built in to every cell. Cells undergoing apoptosis can be recognised because they ................................ in size, the ............................. condenses and organelles such as ................................... break down and become enclosed in extensions of the cell surface membrane called ...................... . The signals for apoptosis may be internal (.............................. ) or external ( ............................ ). A common internal signal is the presence of high levels of oxidants such as .................................... Both internal and external signals eventually result in the destruction and removal of the cell by ...................................... . (9 marks)

Acknowledgements: This Factsheet was researched and written by Ron Pickering. Curriculum Press, Bank House, 105 King Street, Wellington, Shropshire, TF1 1NU. Bio Factsheets may be copied free of charge by teaching staff or students, provided that their school is a registered subscriber. No part of these Factsheets may be reproduced, stored in a retrieval system, or transmitted, in any other form or by any other means, without the prior permission of the publisher. ISSN 1351-5136

2. programmed cell death; decrease/shrink; nucleus; mitochondria; blebs; intrinsic; extrinsic; peroxide ions/superoxide ions; phagocytes; 1. defence against pathogens/with examples (max 3 marks); development of organism/with examples (max 4 marks); in disease management e.g. targeting of tumour cells (1 mark).

Answers