Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

CONTROL OF CELL DIVISION AND CELL GROWTH
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survival. Each is tightly regulated—both by intracellular programs and by extracellular
signal molecules that control these programs.
The extracellular signal molecules that regulate cell growth, division, and
survival are generally soluble secreted proteins, proteins bound to the surface of
cells, or components of the extracellular matrix. They can be divided operationally
into three major classes:
1. Mitogens, which stimulate cell division, primarily by triggering a wave of
G 1 /S-Cdk activity that relieves intracellular negative controls that otherwise
block progress through the cell cycle.
2. Growth factors, which stimulate cell growth (an increase in cell mass) by
promoting the synthesis of proteins and other macromolecules and by
inhibiting their degradation.
3. Survival factors, which promote cell survival by suppressing the form of
programmed cell death known as apoptosis.
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.
Mitogens Stimulate Cell Division
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
mitochondrion
1 µm
microtubule
glycogen
secretory vesicle
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 MBoC6 release m17.61/17.60 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).