A mitogen is a chemical substance that encourages a cell to commence cell division, triggering mitosis. A mitogen is usually some form of protein. Mitogenesis is the induction (triggering) of mitosis, typically via a mitogen. Mitogens trigger signal transduction pathways in which mitogen-activated protein kinase (MAPK) is involved, leading to mitosis.
The cell cycle
Mitogens act primarily by influencing a set of proteins which are involved in the restriction of progression through the cell cycle. The G1 checkpoint is controlled most directly by mitogens: further cell cycle progression does not need mitogens to continue. The point where mitogens are no longer needed to move the cell cycle forward is called the "restriction point" and depends on cyclins to be passed. One of the most important of these is TP53, a gene which produces a family of proteins known as p53. P53, combined with the Ras pathway, downregulate cyclin D1, a cyclin-dependent kinase if they are not stimulated by the presence of mitogens. In the presence of mitogens, sufficient cyclin D1 can be produced. This process cascades onwards, producing other cyclins which stimulate the cell sufficiently to allow reproduction. While animals produce internal signals that can drive the cell cycle forward, external mitogens can cause it to progress without these signals.
Mitogens can be either endogenous or exogenous factors. Endogenous mitogens are used as controlled cell division is a normal and necessary part of the life cycle of multicellular organisms. For example, in zebrafish, an endogenous mitogen Nrg1 is produced in response to indications of heart damage. When it is expressed, it causes the outer layers of the heart to respond by increasing division rates and producing new layers of heart muscle cells to replace the damaged ones. This pathway can have potential deleterious, however; expressing Nrg1 in the absence of heart damage causes uncontrolled growth of heart cells, creating an enlarged heart. Some growth factors, such as vascular endothelial growth factor, are also capable of directly acting as mitogens, causing growth by directly inducing cell replication. This is not true for all growth factors, as some growth factors instead appear to cause mitogenic effects like growth indirectly by triggering other mitogens to be released, as evidenced by their lack of mitogenic activity in vitro, which VEGF has.
Mitogens are important in cancer research due to their effects on the cell cycle. Cancer is in part defined by a lack of, or failure of, control in the cell cycle. Mitogens can contribute to this by causing the cell cycle to move forward when it should be prevented by some mechanism. In normal cells, conditions such as this would be corrected by mechanisms designed to prevent the uncontrolled growth of cells, internal or external, and would result in apoptosis should the cell be unable to repair the damage. In cancerous cells, by some mechanism or other, the ability of the cell to control its own growth is impeded and external mechanisms designed to kill abnormal cells do not function. One system particularly important in the proliferation of cancers is the mitogen-activated protein kinase, or MAPK, system. These proteins have functions that are not related to mitogenesis, but can be triggered by mitogens and do control the cell cycle. MAPK proteins are capable of controlling the cell cycle either to prevent or encourage the growth of cells. The MAPK pathway can be triggered by many ligands, including hormones and growth factors. Some breast cancer types have very high MAPK activity, which is not found even in benign breast tumors. The overexpression of MAP kinase in these cells aids in their proliferation. These are known as hormone-dependent breast cancers, as the MAPK activation in these cancers is connected to exposure to estradiol.
Use in immunology
Lymphocytes can enter mitosis when they are activated by mitogens or antigens. B cells specifically can divide when they encounter an antigen matching their immunoglobulin. T cells undergo mitosis when stimulated by mitogens to produce small lymphocytes that are then responsible for the production of lymphokines, which are substances that modify the host organism to improve its immunity. B cells, on the other hand, divide to produce plasma cells when stimulated by mitogens, which then produce immunoglobulins, or antibodies. Mitogens are often used to stimulate lymphocytes and thereby assess immune function. The most commonly used mitogens in clinical laboratory medicine are:
|Name||Acts upon T cells?||Acts upon B cells?|
|concanavalin A (conA)||yes||no|
|pokeweed mitogen (PWM)||no||yes|
Lipopolysaccharide toxin from gram-negative bacteria is thymus-independent. They may directly activate B cells, regardless of their antigenic specificity. Plasma cells are terminally differentiated and, therefore, cannot undergo mitosis. Memory B cells can proliferate to produce more memory cells or plasma B cells. This is how the mitogen works, that is, by inducing mitosis in memory B cells to cause them to divide, with some becoming plasma cells.
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