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

1116 Chapter 20: Cancer
HYPERPROLIFERATIVE
SIGNALS
DNA
DAMAGE
stable, active p53
TELOMERE
SHORTENING
HYPOXIA
Figure 20–27 Modes of action of the
p53 tumor suppressor. The p53 protein
is a cellular stress sensor. In response to
hyperproliferative signals, DNA damage,
hypoxia, telomere shortening, and various
other stresses, the p53 levels in the cell
rise. As indicated, this may either arrest
cell cycling in a way that allows the cell to
adjust and survive, trigger cell suicide by
apoptosis, or cause cell “senescence”—an
irreversible cell-cycle arrest that stops
damaged cells from dividing.
CELL-CYCLE ARREST SENESCENCE APOPTOSIS
the cell is phagocytosed by its neighbors and its contents are efficiently recycled.
A bad death is a death by necrosis. In necrosis, the cell bursts or disintegrates and
its contents are spilled into the extracellular space, inducing inflammation.
The p53 pathway, therefore, behaves as a sort of antenna, sensing the presence
of a wide range of dangerous MBoC6 m20.40/20.27
conditions, and when any are detected, triggering
appropriate action—either a temporary or permanent arrest of cell cycling
(senescence), or suicide by apoptosis (Figure 20–27). These responses serve to
prevent deranged cells from proliferating. Cancer cells are indeed generally
deranged, and their survival and proliferation thus depend on inactivation of the
p53 pathway. If the p53 pathway were active in them, they would be halted in their
tracks or die (Movie 20.4).
The p53 protein performs its job mainly by acting as a transcription regulator
(see Movie 17.8). Indeed, the most common mutations observed in p53 in human
tumors are in its DNA-binding domain, where they cripple the ability of p53 to
bind to its DNA target sequences. Because p53 binds to DNA as a tetramer, a single
mutant subunit within a tetrameric complex can be enough to block its function.
Thus, mutations in p53 can have a dominant negative effect, causing loss of
p53 function even when the cell also contains a wild-type version of the gene. For
this reason, in contrast with other tumor suppressor genes such as Rb, the development
of cancer does not always require that both copies of p53 be knocked out.
As discussed in Chapter 17, the p53 protein exerts its inhibitory effects on the
cell cycle, in part at least, by inducing the transcription of p21, which encodes a
protein that binds to and inhibits the cyclin-dependent kinase (Cdk) complexes
required for progression through the cell cycle. By blocking the kinase activity of
these Cdk complexes, the p21 protein prevents the cell from progressing through
S phase and replicating its DNA.
The mechanism by which p53 induces apoptosis includes stimulation of the
expression of many pro-apoptotic genes, and it will be described in Chapter 18.
Genome Instability Takes Different Forms in Different Cancers
If the p53 pathway is functional, a cell with unrepaired DNA damage will stop
dividing or die; it cannot proliferate. Mutations in the p53 pathway are, therefore,
generally present in cancer cells showing genome instability—which is to say,
the majority. But how does this genome instability originate? Here too, cancer
genome studies are illuminating.
In ovarian cancers, for example, chromosome breaks, translocations, and
deletions are very common, and these aberrations correlate with a high frequency
of mutations and epigenetic silencing in the genes needed for repair of DNA double-strand
breaks by homologous recombination, especially Brca1 and Brca2 (see
pp. 281–282). In a subset of colorectal cancers with DNA mismatch repair defects,
on the other hand, one instead finds many point mutations scattered throughout
the genome (see pp. 250–251). In both kinds of cancer, the genome is commonly
destabilized, but different types of mutations can bring this about.