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

1016 Chapter 17: The Cell Cycle
Many Human Cells Have a Built-In Limitation on the Number of
Times They Can Divide
Many human cells divide a limited number of times before they stop and undergo
a permanent cell-cycle arrest. Fibroblasts taken from normal human tissue, for
example, go through only about 25–50 population doublings when cultured in
a standard mitogenic medium. Toward the end of this time, proliferation slows
down and finally halts, and the cells enter a nondividing state from which they
never recover. This phenomenon is called replicative cell senescence.
Replicative cell senescence in human fibroblasts seems to be caused by
changes in the structure of the telomeres, the repetitive DNA sequences and associated
proteins at the ends of chromosomes. As discussed in Chapter 5, when a
cell divides, telomeric DNA sequences are not replicated in the same manner as
the rest of the genome but instead are synthesized by the enzyme telomerase.
Telomerase also promotes the formation of protein cap structures that protect the
chromosome ends. Because human fibroblasts, and many other human somatic
cells, do not produce telomerase, their telomeres become shorter with every cell
division, and their protective protein caps progressively deteriorate. Eventually,
the exposed chromosome ends are sensed as DNA damage, which activates
a p53-dependent cell-cycle arrest (see Figure 17–62). Rodent cells, by contrast,
maintain telomerase activity when they proliferate in culture and therefore do not
have such a telomere-dependent mechanism for limiting proliferation. The forced
expression of telomerase in normal human fibroblasts, using genetic engineering
techniques, blocks this form of senescence. Unfortunately, most cancer cells
have regained the ability to produce telomerase and therefore maintain telomere
function as they proliferate; as a result, they do not undergo replicative cell senescence.
Abnormal Proliferation Signals Cause Cell-Cycle Arrest or
Apoptosis, Except in Cancer Cells
Many of the components of mitogenic signaling pathways are encoded by genes
that were originally identified as cancer-promoting genes, because mutations in
them contribute to the development of cancer. The mutation of a single amino
acid in the small GTPase Ras, for example, causes the protein to become permanently
overactive, leading to constant stimulation of Ras-dependent signaling
pathways, even in the absence of mitogenic stimulation. Similarly, mutations that
cause an overexpression of Myc stimulate excessive cell growth and proliferation
and thereby promote the development of cancer (discussed in Chapter 20).
Surprisingly, however, when a hyperactivated form of Ras or Myc is experimentally
overproduced in most normal cells, the result is not excessive proliferation
but the opposite: the cells undergo either permanent cell-cycle arrest or
apoptosis. The normal cell seems able to detect abnormal mitogenic stimulation,
and it responds by preventing further division. Such responses help prevent the
survival and proliferation of cells with various cancer-promoting mutations.
Although it is not known how a cell detects excessive mitogenic stimulation,
such stimulation often leads to the production of a cell-cycle inhibitor protein
called Arf, which binds and inhibits Mdm2. As discussed earlier, Mdm2 normally
promotes p53 degradation. Activation of Arf therefore causes p53 levels to
increase, inducing either cell-cycle arrest or apoptosis (Figure 17–63).
How do cancer cells ever arise if these mechanisms block the division or survival
of mutant cells with overactive proliferation signals? The answer is that the
protective system is often inactivated in cancer cells by mutations in the genes
that encode essential components of the blocking mechanisms, such as Arf or p53
or the proteins that help activate them.
Cell Proliferation is Accompanied by Cell Growth
If cells proliferated without growing, they would get progressively smaller and
there would be no net increase in total cell mass. In most proliferating cell populations,
therefore, cell growth accompanies cell division. In single-celled organisms