Key concepts

• Organisms attempt to block the development of cancer through the actions of the
p53 alarm protein, which can cause cells to enter quiescence or apoptosis in the
event that the machinery regulating cell proliferation is malfunctioning or the cell
is exposed to various types of physiologic stress.
• p53 is a nuclear protein that normally exists as a tetramer and functions as a transcription
factor.
The mutant p53 found in many human tumors usually carries amino acid substitutions
in its DNA-binding domain. When mutant p53 forms tetrameric complexes
with wild-type p53, it interferes with the normal functions of the wild-type subunits
and thus with functions of the tetramer as a whole.
• p53 can impose cell cycle arrest through its ability to induce expression of p21 Cip1,
and apoptosis through its ability to induce expression of a variety of pro-apoptotic
proteins.
• p53 normally turns over rapidly. This turnover is blocked when a variety of signals
indicate cell-physiologic stress, including anoxia, damage to the genome, and signaling
imbalances in the intracellular growth-regulating machinery.
• p53 becomes functionally activated when its normally rapid degradation is
blocked. In addition, covalent modifications of the resulting accumulated p53
protein modulate its activity as a transcription factor, directing it to activate the
expression of genes involved in various cellular responses, notably apoptosis,
cytostasis, and senescence.
• p53 levels are controlled by two critical upstream regulators, Mdm2 and p19ARF.
Mdm2 works to destroy p53, while ARF inhibits Mdm2 from acting.
• Excessive activity of E2Fs, which is triggered by deregulation of the pRb pathway,
results in activation of ARF and thus p53.
• Apoptosis involves the activation of a cascade of caspases that results in the
destruction of a cell, usually within an hour. It can be activated by p53 as well as
signals impinging on the cell from the outside, notably those transduced by cell
surface death receptors.
• The apoptotic caspase cascade can be triggered through the opening of a channel
in the outer membrane of mitochondria, which releases several pro-apoptotic
proteins, notably cytochrome c.
• Opening of the mitochondrial membrane channel is determined by the relative
levels of Bcl-2–related anti-apoptotic and pro-apoptotic proteins.
• Loss of apoptotic functions allows cancer cells to survive a variety of cell-physiologic
stresses, including anoxia, signaling imbalances, DNA damage, and loss of
anchorage.
• Cancer cells invent numerous ways to inactivate the apoptotic machinery in order
to survive and thrive. Included among these are activation of Akt/PKB firing,
increase in the levels of anti-apoptotic Bcl-2–related proteins, inactivation of p53
through changes in the p53 gene or the upstream regulators of p53, methylation of
the promoters of a variety of pro-apoptotic genes, interference with cytochrome c
release from mitochondria, and inhibition of caspases.