Cell Structure and Genetic Control 75membranes, and burst. Such cellular death, leading to tissue
death, is known as necrosis. In certain cases, however, a differ-
ent pattern is observed. Instead of swelling, the cells shrink. The
membranes remain intact but become bubbled, and the nuclei
condense. This process was named apoptosis (from a Greek term
describing the shedding of leaves from a tree), and its discoverers
were awarded the 2002 Nobel Prize in Physiology or Medicine.
There are two pathways that lead to apoptosis: extrinsic
and intrinsic. In the extrinsic pathway, extracellular molecules
called death ligands bind to receptor proteins on the plasma
membrane called death receptors. An example of a death recep-
tor is one known as FAS; the death ligand that binds to it is
called FASL.
In the intrinsic pathway, apoptosis occurs in response to
intracellular signals. This may be triggered by DNA damage,
for example, or by reactive oxygen species that cause oxidative
stress (discussed in chapters 5 and 19). Cellular stress signals
produce a sequence of events that make the outer mitochon-
drial membrane permeable to cytochrome c and some other
mitochondrial molecules, which leak into the cytoplasm and
participate in the next phase of apoptosis.
The intrinsic and extrinsic pathways of apoptosis both
result in the activation of a group of previously inactive cyto-
plasmic enzymes known as caspases. Caspases have been
called the “executioners” of the cell, activating processes that
lead to fragmentation of the DNA and death of the cell. Apop-
tosis is a normal, physiological process that also helps the body
rid itself of cancerous cells with damaged DNA.
Apoptosis occurs normally as part of programmed cell
death—a process described previously in the section on lyso-
somes. Programmed cell death is the physiological process
responsible for the remodeling of tissues during embryonic
development and for tissue turnover in the adult body. As men-
tioned earlier, the epithelial cells lining the digestive tract are
programmed to die two to three days after they are produced,
and epidermal cells of the skin live only for about two weeks
until they die and become completely cornified. Apoptosis is
also important in the functioning of the immune system. A
neutrophil (a type of white blood cell), for example, is pro-
grammed to die by apoptosis 24 hours after its creation in the
bone marrow. A killer T lymphocyte (another type of white
blood cell) destroys targeted cells by triggering their apoptosis.
When a cell is dying by apoptosis, it releases chemicals
that attract phagocytic macrophages (section 3.1). Macro-
phages recognize and eat dead cells, sparing the healthy cells.
This is because the apoptotic cell displays a molecule (phos-
phatidylserine) present on the inner layer of the plasma mem-
brane. When the membrane is disrupted and this molecule is
exposed to macrophages, it functions as an “eat me” signal.
Macrophages engulf the dead cell and digest it within lyso-
somes, thereby preventing the interior contents of the apoptotic
cell from being released into the extracellular environment and
activating an immune response.
Using mice with their gene for p53 knocked out, scien-
tists have learned that p53 is needed for the apoptosis that
occurs when a cell’s DNA is damaged. DNA damage occursOveractivity of a gene that codes for a cyclin D might be pre-
dicted to cause uncontrolled cell division, as occurs in a cancer.
Indeed, overexpression of the gene for cyclin D1 has been shown
to occur in some cancers, including those of the breast and esoph-
agus. Genes that contribute to cancer are called oncogenes. Onco-
genes are altered forms of normal proto-oncogenes, which code
for proteins that control cell division and apoptosis (cell suicide,
discussed shortly). Conversion of proto-oncogenes to active onco-
genes occurs because of genetic mutations and chromosome rear-
rangements (including translocations and inversions of particular
chromosomal segments in different cancers).
Whereas oncogenes promote cancer, other genes—called
tumor suppressor genes —inhibit its development. One very
important tumor suppressor gene is known as p53. This name
refers to the protein coded by the gene, which has a molecular
weight of 53,000. The p53 is a transcription factor: a protein
that can bind to DNA and activate or repress a large number
of genes. When there is damage to DNA, p53 acts to stall cell
division, mainly at the G 1 to S checkpoint of the cell cycle.
Depending on the situation, p53 could help repair DNA while
the cell cycle is arrested, or it could help promote apoptosis
(cell death) so that the damaged DNA isn’t replicated and
passed on to daughter cells.
Through these and other mechanisms, the normal p53 gene
protects against cancer caused by damage to DNA through radi-
ation, toxic chemicals, or other cellular stresses. The ability of
p53 to suppress cancer by causing cell cycle arrest or apoptosis
is reduced in over 50% of all cancers. In about half of these
cases, the gene for p53 is mutated, usually by a “point muta-
tion” that causes a change in a single amino acid in the p53 pro-
tein. In the other half of cancers associated with inadequate p53
action, the p53 is normal but its ability to function is reduced.
This can occur if there are defects in other proteins needed for
p53 to function. Scientists are currently investigating molecules
that might restore p53 activity as potential treatments for cancer.
Experimental mice with their gene for p53 “knocked out”
all developed tumors. The 2007 Nobel Prize in Physiology or
Medicine was awarded to the scientists who developed knockout
mice —strains of mice in which a specific, targeted gene has been
inactivated. This is done using mouse embryonic stem cells (chap-
ter 20, section 20.6), which can be grown in vitro. A defective
copy of the gene is made and introduced into the embryonic stem
cells, which are then put into a normal (wild-type) embryo. The
mouse that develops from this embryo is a chimera, or mixture of
the normal and mutant types. Because all of this chimera’s tissues
contain cells with the inactivated gene, this mutation is also pres-
ent in some of its gametes (sperm or ova). Therefore, when this
mouse is mated with a wild-type mouse, some of the progeny (and
their subsequent progeny) will have the targeted gene “knocked
out.” This technique is now widely used to help determine the
physiological importance of gene products, such as p53.
Cell Death
Cell death occurs both pathologically and naturally. Pathologi-
cally, cells deprived of a blood supply may swell, rupture their