section 26.6
Regulation of Cell Proliferation: Oncogenes
609
hormones are not capable of penetrating the target cells,
and instead the binding of a hormone to a membrane re-
ceptor induces intracellular synthesis of cAMP and other
second messengers; these second messengers then cause
the desired metabolic effects (Chapter 30).
26.5 Regulation of Cell Death: Apoptosis
Apoptosis
(programmed cell death) is characterized by
a complex series of biochemical changes that culminate
in cell death without inflammation or swelling, which are
signs of necrosis. Embryonic, fetal, and postnatal develop-
ment involve cell death by apoptosis, which serves to elim-
inate excessive cell proliferation and migration. Apoptosis
is initiated by a variety of external stimuli and molecular
events such as oxidative stress, mitochondrial permeability
transition, mitochondrial cytochrome c release, activation
of caspase proteases, activation of endonucleases, transg-
lutaminase activation, and poly(ADP-ribose) polymerase
cleavage.
Necrosis
is a form of passive cell death that is very
distinct from apoptosis and usually occurs in a regional
group of cells after a particular event, such as stroke, in-
farction, hemorrhage, or infection. In contrast to necrosis,
apoptosis is an active process requiring RNA synthesis,
protein synthesis, and new enzyme activities. Apoptosis
usually involves isolated single cells that may undergo
programmed cell death in a particular organ at different
times. Certain features of a cell undergoing death by apop-
tosis distinguish it from one dying by necrosis. First, the
cell shrinks, the plasma membrane and vesiculates change
shape, and phosphatidylserine is redistributed on the cell
surface. Specific nuclear changes also are diagnostic of
a cell undergoing death by apoptosis. Nuclear fragmen-
tation occurs from chromatin condensation and internu-
cleosomal DNA breakdown. Analysis of the DNA shows
a laddering fragment pattern that is the result of abnor-
mally activated endonucleases. Although apoptosis is es-
sential to normal development, it also appears to be the
cause of pathogenic changes in several chronic neuro-
logical diseases including
amyotrophic lateral sclerosis
(ALS),
Parkinson’s disease, Huntington’s disease,
and
spinocerebellar ataxias.
Apoptosis also may play a key
role in the development of Alzheimer’s disease.
Regardless of the activating signal for apoptosis, dying
cells follow the same series of events.
Caspase
proteinases
play a central role in apoptosis; they are cysteine pro-
teinases that are activated by apoptotic signals and degrade
cellular proteins by cleavage after aspartate residues. The
first caspase discovered (caspase-
1
) in mammalian cells
was recognized as a “cell death” enzyme by its similarity
to the cell death gene,
ced-3,
in the nematode
Caenorhab-
ditis elegans.
Subsequent studies have identified almost a
dozen mammalian caspases that function as apoptotic ini-
tiators (caspases 2 ,8 ,9 ,
1 0
), apoptotic executioners (cas-
pases 3,6,7), and cytokine processors (caspases 1,4,5).
Activation of caspases 1 and 3 appears to play a key role
in the pathogenesis of chronic neurological diseases re-
sulting from progressive cell death. On the other hand,
caspase inactivation appears to promote oncogenesis by
allowing cell accumulation. Thus, caspases are prime tar-
gets for intervention in a variety of diseases that progress
to death.
ALS was first described by the French neurologist
Charpot in 1869. The disease involves rapid loss of motor
neurons in the cortex, brain stem, and spinal cord; death
usually follows 3-5 years after diagnosis. ALS is more
commonly referred to as
Lou Gehrig’s disease
because it
struck down the New York Yankees immortal at the peak of
his baseball career. ALS usually occurs in a sporadic form
but in rare cases there is a familial factor; this provided the
first clues to the molecular basis for ALS.
One form of ALS results from mutations in the
SOM
gene that codes for the cystolic enzyme copper/zinc
super-
oxide dismutase
(Cu,Zn-SOD). Mice lacking this enzyme
do not develop ALS but mice that overexpress the mu-
tant gene do develop symptoms characteristic of ALS and
motor neuron death. It is now known that a mutant
SOD1
gene causes apoptotic motor neuron death by activating
initiator caspases. Using drugs that inhibit caspase activ-
ity in ALS transgenic mice, the life span of the mice has
been increased by about 70%. As more molecular details
of caspase functions and apoptosis in cancer and neuro-
logical diseases are revealed, it eventually may be possible
to develop drugs that ameliorate or suppress symptoms of
these deadly diseases.
26.6 Regulation of Cell Proliferation: Oncogenes
In the course of differentiation, most adult cell types of
higher eukaryotes lose the ability to divide. Only a small
number of cell types, (e.g., cells of the intestinal mucosa,
erythropoietic cells, and male germline cells) continue to
do so. Many genes and regulatory elements determine
whether a cell can or cannot divide. However, a class of
genes has been discovered that, in certain circumstances,
restores the ability of the cells to divide and, more signifi-
cantly, to do so with little or no control. These
oncogenes
have been detected in many tumors and in RNA and DNA
oncogenic viruses that cause cancers in infected animals.
The first oncogene discovered was
src,
a gene carried by
Rous sarcoma virus
that causes sarcomas in infected fowl.
