Concept 11.5: Apoptosis integrates multiple cell-signaling pathways Flashcards
When signaling pathways were first discovered, they were thought to be
linear, independent pathways.
For a cell to carry out the appropriate response, cellular proteins often must integrate
multiple signals.
Cells that are infected, are damaged, or have reached the end of their functional life span often undergo
“programmed cell death”
The best-understood type of this controlled cell suicide is
apoptosis
During this process, cellular agents chop up the
DNA and fragment the organelles and other cytoplasmic components
The cell shrinks and becomes lobed (a change called “blebbing”), and the cell’s parts are packaged up in vesicles that are
engulfed and digested by specialized scavenger cells, leaving no trace
Apoptosis protects neighboring cells from damage that they would otherwise suffer if a dying cell merely leaked out all its contents, including its many
digestive enzymes.
The signal that triggers apoptosis can come from either
outside or inside the cell.
Outside the cell, signaling molecules released from other cells can initiate a
signal transduction pathway that activates the genes and proteins responsible for carrying out cell death.
Within a cell whose DNA has been irretrievably damaged, a series of protein-protein interactions can
pass along a signal that similarly triggers cell death
The molecular mechanisms of apoptosis were worked out by researchers studying embryonic development of a small soil worm, a nematode called
Caenorhabditis elegans
The timely suicide of cells occurs exactly
131 times during normal development of C. elegans, at precisely the same points in the cell lineage of each worm.
In worms and other species, apoptosis is triggered by signals that activate a
cascade of “suicide” proteins in the cells destined to die.
Genetic research on C. elegans initially revealed two key apoptosis genes, called
ced-3 and ced-4 (ced stands for “cell death”), which encode proteins essential for apoptosis.
These and most other proteins involved in apoptosis are continually present in cells, but in inactive form;
thus, regulation in this case occurs at the level of protein activity rather than through gene activity and protein synthesis.
In C. elegans, a protein in the outer mitochondrial membrane, called
Ced-9 (the product of the ced-9 gene), serves as a master regulator of apoptosis, acting as a brake in the absence of a signal promoting apoptosis
When a death signal is received by the cell, signal transduction involves a change in
Ced-9 that disables the brake, and the apoptotic pathway activates proteases and DNA of the cell
The main proteases of apoptosis are called ___________ ; in the nematode, the chief caspase is the Ced-3 protein.
caspases
In humans and other mammals, several different pathways, involving about
15 different caspases, can carry out apoptosis.
The pathway that is used depends on the type of
cell and on the particular signal that initiates apoptosis.
One major pathway involves certain mitochondrial proteins that are triggered to form molecular pores in the mitochondrial outer membrane, causing it to
leak and release other proteins that promote apoptosis
Perhaps surprisingly, these latter include
cytochrome c, which functions in mitochondrial electron transport in healthy cells (see Figure 9.15) but acts as a cell death factor when released from mitochondria.
The process of mitochondrial apoptosis in mammals uses proteins similar to the nematode proteins
Ced-3, Ced-4, and Ced-9.
These can be thought of as relay proteins capable of
transducing the apoptotic signal.
At key gateways into the apoptotic program, relay proteins integrate signals from several different sources and can send a cell
down an apoptotic pathway
Often, the signal originates outside the cell, like the death-signaling molecule depicted in Figure 11.20b, which presumably was released by a
neighboring cell.
When a death-signaling ligand occupies a cell-surface receptor, this binding leads to activation of .
caspases and other enzymes that carry out apoptosis, without involving the mitochondrial pathway
In a twist on the classic scenario, two other types of alarm signals that can lead to apoptosis originate from inside the cell rather than from a
cell-surface receptor.
One signal comes from the
nucleus, generated when the DNA has suffered irreparable damage,
a second comes from the
endoplasmic reticulum when excessive protein misfolding occurs.
Mammalian cells make life-or-death “decisions” by somehow integrating the death signals and life signals they receive from these
external and internal sources.
A built-in cell suicide mechanism is essential to
development and maintenance in all animals.
The similarities between apoptosis genes in nematodes and those in mammals, as well as the observation that apoptosis occurs in multicellular fungi and even in single-celled yeasts, indicate that the basic mechanism evolved
early in the evolution of eukaryotes
In vertebrates, apoptosis is essential for normal development of the nervous system, for normal operation of the immune system, and for normal
morphogenesis of hands and feet in humans and paws in other mammals
The level of apoptosis between the developing digits is lower in the webbed feet of ducks and other water birds than in the nonwebbed
feet of land birds, such as chickens
In the case of humans, the failure of appropriate apoptosis can result in .
webbed fingers and toes
Significant evidence points to the involvement of apoptosis in certain degenerative diseases of the nervous system, such as
Parkinson’s disease and Alzheimer’s disease.
In Alzheimer’s disease, an accumulation of aggregated proteins in neuronal cells activates an enzyme that triggers apoptosis, resulting in the
loss of brain function seen in these patients.
Furthermore, cancer can result from a failure of
cell suicide;
some cases of human melanoma, for example, have been linked to
faulty forms of the human version of the C. elegans Ced-4 protein
