Many extracellular signal molecules promote all of these processes, while others promote one or two of them. Indeed, the term growth factor is often used inappropriately to describe a factor that has any of these activities. Even worse, the term cell growth is often used to mean an increase in cell number, or cell proliferation.
In addition to these three classes of stimulating signals, there are extracellular signal molecules that suppress cell proliferation, cell growth, or both; in general, less is known about them. There are also extracellular signal molecules that activate apoptosis.
In this section, we focus primarily on how mitogens and other factors, such as DNA damage, control the rate of cell division. We then turn to the important but poorly understood problem of how a proliferating cell coordinates its growth with cell division so as to maintain its appropriate size. We discuss the control of cell survival and cell death by apoptosis in Chapter 18.
Unicellular organisms tend to grow and divide as fast as they can, and their rate of proliferation depends largely on the availability of nutrients in the environment. The cells of a multicellular organism, however, divide only when the organism needs more cells. Thus, for an animal cell to proliferate, it must receive stimulatory extracellular signals, in the form of mitogens, from other cells, usually its neighbors. Mitogens overcome intracellular braking mechanisms that block progress through the cell cycle.
One of the first mitogens to be identified was platelet-derived growth factor (PDGF), and it is typical of many others discovered since. The path to its isolation began with the observation that fibroblasts in a culture dish proliferate when provided with serum but not when provided with plasma. Plasma is prepared by removing the cells from blood without allowing clotting to occur; serum is prepared by allowing blood to clot and taking the cell-free liquid that remains. When blood clots, platelets incorporated in the clot are stimulated to release the contents of their secretory vesicles (Figure 17–60). The superior ability of serum to support cell proliferation suggested that platelets contain one or more mitogens. This hypothesis was confirmed by showing that extracts of platelets could serve instead of serum to stimulate fibroblast proliferation. The crucial factor in the extracts was shown to be a protein, which was subsequently purified and named PDGF. In the body, PDGF liberated from blood clots helps stimulate cell division during wound healing.
PDGF is only one of over 50 animal proteins that are known to act as mitogens. Most of these proteins have a broad specificity. PDGF, for example, can stimulate many types of cells to divide, including fibroblasts, smooth muscle cells, and neuroglial cells. Similarly, epidermal growth factor (EGF ) acts not only on epidermal cells but also on many other cell types, including both epithelial and nonepithelial cells. Some mitogens, however, have a narrow specificity; erythropoietin, for
Figure 17–60 A platelet. platelets are miniature cells without a nucleus. They circulate in the blood and help stimulate blood clotting at sites of tissue damage, thereby preventing excessive bleeding. They also release various factors that stimulate wound healing. The platelet shown here has been cut in half to show its secretory vesicles, some of which contain platelet-derived growth factor (pdgF).
example, only induces the proliferation of red blood cell precursors. Many mitogens, including PDGF, also have actions other than the stimulation of cell division: they can stimulate cell growth, survival, differentiation, or migration, depending on the circumstances and the cell type.
In some tissues, inhibitory extracellular signal proteins oppose the positive regulators and thereby inhibit organ growth. The best-understood inhibitory signal proteins are transforming growth factor-β (TGFβ) and its relatives. TGFβ inhibits the proliferation of several cell types, mainly by blocking cell-cycle progression in G1.