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

1012 Chapter 17: The Cell Cycle
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 G 1 .
Cells Can Enter a Specialized Nondividing State
In the absence of a mitogenic signal to proliferate, Cdk inhibition in G 1 is maintained
by the multiple mechanisms discussed earlier, and progression into a new
cell cycle is blocked. In some cases, cells partly disassemble their cell-cycle control
system and withdraw from the cycle to a specialized nondividing state called
G 0 .
Most cells in our body are in G 0 , but the molecular basis and reversibility of
this state vary in different cell types. Most of our neurons and skeletal muscle cells,
for example, are in a terminally differentiated G 0 state, in which their cell-cycle
control system is completely dismantled: the expression of the genes encoding
various Cdks and cyclins is permanently turned off, and cell division rarely occurs.
Some cell types withdraw from the cell cycle only transiently and retain the ability
to reassemble the cell-cycle control system quickly and re-enter the cycle. Most
liver cells, for example, are in G 0 , but they can be stimulated to divide if the liver
is damaged. Still other types of cells, including fibroblasts and some lymphocytes,
withdraw from and re-enter the cell cycle repeatedly throughout their lifetime.
Almost all the variation in cell-cycle length in the adult body occurs during the
time the cell spends in G 1 or G 0 . By contrast, the time a cell takes to progress from
the beginning of S phase through mitosis is usually brief (typically 12–24 hours in
mammals) and relatively constant, regardless of the interval from one division to
the next.
Mitogens Stimulate G 1 -Cdk and G 1 /S-Cdk Activities
For the vast majority of animal cells, mitogens control the rate of cell division by
acting in the G 1 phase of the cell cycle. As discussed earlier, multiple mechanisms
act during G 1 to suppress Cdk activity. Mitogens release these brakes on Cdk
activity, thereby allowing entry into a new cell cycle.
As we discuss in Chapter 15, mitogens interact with cell-surface receptors to
trigger multiple intracellular signaling pathways. One major pathway acts through
the monomeric GTPase Ras, which leads to the activation of a mitogen-activated
protein kinase (MAP kinase) cascade (see Figure 15–49). This leads to an increase
in the production of transcription regulatory proteins, including Myc. Myc is
thought to promote cell-cycle entry by several mechanisms, one of which is to
increase the expression of genes encoding G 1 cyclins (D cyclins), thereby increasing
G 1 -Cdk (cyclin D–Cdk4) activity. Myc also has a major role in stimulating the
transcription of genes that increase cell growth.
The key function of G 1 -Cdk complexes in animal cells is to activate a group
of gene regulatory factors called the E2F proteins, which bind to specific DNA
sequences in the promoters of a wide variety of genes that encode proteins required
for S-phase entry, including G 1 /S-cyclins, S-cyclins, and proteins involved in DNA
synthesis and chromosome duplication. In the absence of mitogenic stimulation,
E2F-dependent gene expression is inhibited by an interaction between E2F and
members of the retinoblastoma protein (Rb) family. When cells are stimulated
to divide by mitogens, active G 1 -Cdk accumulates and phosphorylates Rb family
members, reducing their binding to E2F. The liberated E2F proteins then activate
expression of their target genes (Figure 17–61).
This transcriptional control system, like so many other control systems that
regulate the cell cycle, includes feedback loops that ensure that entry into the