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Chapter 17 Control of Cell Division 183

R
Competence Restriction Point

M Progression G 1 /S S
Mitosis G 1 pm G 1 ps DNA Synthesis

G 0 G 1 /S
Quiescence Checkpoint

Terminal differentiation Senescence
A

R
Competence Restriction Point
Mono–phosphorylated RB Hyper–phosphorylated RB
M Cyclin D – CDK4 Cyclin E – CDK2 S
Mitosis p27 Growth PI3K MTOR p53 p21 DNA Synthesis
factors
G 1 /S
G 0
Quiescence Checkpoint
Un–phosphorylated RB p53 p21
DREAM p16
Terminal differentiation Senescence
B
Fig. 17.5 CHECKPOINTS OF CELL CYCLE ENTRY. (A) Quiescence is a nonproliferative state in which
viable cells have left the cell cycle and may remain for prolonged periods. In contrast, terminally differentiated
cells have irreversibly exited the cell cycle during the process of differentiation. When cells sense that conditions
are suitable for proliferation, they leave quiescence into G 1 phase and become competent to enter the cell
cycle. G 1 has been subdivided into segments, and a particularly important point is the restriction point, or R,
which occurs near the G 1 –S boundary. The period after mitosis, when cells can enter quiescence, is termed
G 1 pm (postmitosis), and the period between quiescence and S phase is termed G 1 ps (pre-DNA synthesis).
When DNA damage is recognized in G 1 , the G 1 /S checkpoint becomes activated, which blocks cells from
S-phase entry, although they may have passed the restriction point. If damage is not repaired in a timely
manner, cells will enter senescence, where they remain viable but not capable of reentering the cell cycle. (B)
During quiescence, the cyclin-dependent kinase (CDK) inhibitor p27 prevents cyclin-CDK activity, and
dimerization partner, RB-like, E2F, and multivulval class B (DREAM) and retinoblastoma protein (RB) bind
and repress cell cycle genes. When prompted by growth signals, cells enter the competent state. Activation of
RAS–mitogen-activate protein kinase and phosphoinositol 3-kinase (PI3K) signaling pathways is followed by
activation of cyclin D–CDK4/6, leading to monophosphorylation of RB. The progressive decrease in p27
protein levels during G 1 allows for activation of cyclin E–CDK2, which multiphosphorylate the monophos-
phorylated RB, leading to the release of the activating E2F transcription factors. When DNA damage is
recognized in G 1 , p53 becomes activated, and the p53 target gene p21 promotes cell cycle arrest at the G 1 /S
transition through inhibition of cyclin E–CDK2 and activation of RB. Also, p16 can become activated by
oncogenic stress, which leads to inhibition of cyclin D–CDK4/6 and activation of the G 1 /S checkpoint. If
stress signaling is not relieved, cells will enter a senescent state. MTOR, Mammalian target of rapamycin.

However, this initial increase in MAPK activity does not lead to contributions of signaling by MAPK, PI3K, and MYC to enable cell
induction of MYC and cyclin D; it leads only to the presence of growth, it also became clear that there are restraining activities that
growth signals several hours later that activate the PI3K pathway and can inhibit cell cycle entry and progression. As mentioned earlier,
MYC. Functions of MYC include transcriptional activation of CDK4 cyclin D levels increase during the progression phase of G 1 , and cyclin
and Cyclin D, as well as downregulation of CDK inhibitors. The D–CDK4/6 complexes monophosphorylate RB, which restricts the
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following increase in cyclin D–CDK4 complex activity leads to activating E2F transcription factors. Later in G 1 , cyclin E levels
phosphorylation of the principal target RB during G 1 phase. increase, and cyclin E binds specifically to CDK2. This leads to RB
hyperphosphorylation and release of the activating E2Fs, enabling
E2F-dependent gene expression. Once past this point, growth factors
Restriction Point are no longer required for S-phase entry. Therefore expression and
activation of cyclin E–CDK2 resulting in the hyperphosphorylation
In 1974, Arthur Pardee published the first report on the restriction of RB enables a cell to pass the restriction point and become com-
point, and defined it as a point at which cells become committed to mitted to cell cycle entry.
entering S phase, regardless of subsequent availability of growth
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factors or essential nutrients. He also correctly predicted that cancer
cells undergo changes that lose the dependency on growth factors and G 1 /S Checkpoint
are not dependent on the restriction point. In the four decades that
have passed since the initial description of the restriction point, many The G 1/S DNA damage checkpoint can be viewed as a point in the
important insights have been gained that revealed the signaling events cell cycle when the cell has become fully committed to enter into S
that contribute to proliferation and growth. In addition to the key phase and past the restriction point, but is unable to enter S phase