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| Cell Cycle |
Normal cells grow and divide in an orderly fashion, in accordance with the cell cycle. (Mutations in proto-oncogenes or in tumor suppressor genes allow a cancerous cell to grow and divide without the normal controls imposed by the cell cycle.) The major events in the cell cycle are described in Fig. 2.
Several proteins control the timing of the events in the cell cycle, which is tightly regulated to ensure that cells divide only when necessary. The loss of this regulation is the hallmark of cancer. Major control switches of the cell cycle are cyclin-dependent kinases. Each cyclin-dependent kinase forms a complex with a particular cyclin, a protein that binds and activates the cyclin-dependent kinase. The kinase part of the complex is an enzyme that adds a phosphate to various proteins required for progression of a cell through the cycle. These added phosphates alter the structure of the protein and can activate or inactivate the protein, depending on its function. There are specific cyclin-dependent kinase/cyclin complexes at the entry points into the G1, S, and M phases of the cell cycle, as well as additional factors that help prepare the cell to enter S phase and M phase.
One important protein in the cell cycle is p53, a transcription factor (see Genetics of Development unit) that binds to DNA, activating transcription of a protein called p21. P21 blocks the activity of a cyclin-dependent kinase required for progression through G1. This block allows time for the cell to repair the DNA before it is replicated. If the DNA damage is so extensive that it cannot be repaired, p53 triggers the cell to commit suicide. The most common mutation leading to cancer is in the gene that makes p53.
Li-Fraumeni syndrome, an inherited predisposition to multiple cancers, results from a germ line (egg or sperm) mutation in p53. Other proteins that stop the cell cycle by inhibiting cyclin dependent kinases are p16 and RB. All of these proteins, including p53, are tumor suppressors.
Cancer cells do not stop dividing, so what stops a normal cell from dividing? In terms of cell division, normal cells differ from cancer cells in at least four ways.
- Normal cells require external growth factors to divide. When synthesis of these growth factors is inhibited by normal cell regulation, the cells stop dividing. Cancer cells have lost the need for positive growth factors, so they divide whether or not these factors are present. Consequently, they do not behave as part of the tissue - they have become independent cells.
- Normal cells show contact inhibition; that is, they respond to contact with other cells by ceasing cell division. Therefore, cells can divide to fill in a gap, but they stop dividing as soon as there are enough cells to fill the gap. This characteristic is lost in cancer cells, which continue to grow after they touch other cells, causing a large mass of cells to form.
- Normal cells age and die, and are replaced in a controlled and orderly manner by new cells. Apoptosis is the normal, programmed death of cells. Normal cells can divide only about fifty times before they die. This is related to their ability to replicate DNA only a limited number of times. Each time the chromosome replicates, the ends (telomeres) shorten. In growing cells, the enzyme telomerase replaces these lost ends. Adult cells lack telomerase, limiting the number of times the cell can divide. However, telomerase is activated in cancer cells, allowing an unlimited number of cell divisions.
- Normal cells cease to divide and die when there is DNA damage or when cell division is abnormal. Cancer cells continue to divide, even when there is a large amount of damage to DNA or when the cells are abnormal. These progeny cancer cells contain the abnormal DNA; so, as the cancer cells continue to divide they accumulate even more damaged DNA.