A mitogen is a small bioactive protein or peptide that induces a cell to begin cell division, or enhances the rate of division (mitosis). Mitogenesis is the induction (triggering) of mitosis, typically via a mitogen. The mechanism of action of a mitogen is that it triggers signal transduction pathways involving mitogen-activated protein kinase (MAPK), 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. It, 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 cell division. While animals produce internal signals that can drive the cell cycle forward, external mitogens can cause it to progress without these signals. Endogenous mitogens Mitogens can be either endogenous or exogenous factors. Endogenous mitogens function to control 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 potentially be 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. Other well-known mitogenic growth factors include platelet derived growth factor (PDGF) and epidermal growth factor