Download Types of Programmed Cell Death The mechanisms by which cells

Types of Programmed Cell Death
The mechanisms by which cells die can be divided into two general types:
programmed cell death (PCD) mechanisms that require energy, and necrotic cell
death mechanisms that do not (Elmore, 2007). One type of PCD is apoptosis,
where, in response to extrinsic or intrinsic death signals, pro-apoptotic factors
such as cytochrome C are released from the mitochondria, a cascade of
proteases (called caspases) are activated, and the cell undergoes a series of
characteristic morphological and biochemical changes including shrinkage,
membrane blebbing, and DNA fragmentation. Cell death signals can be
intracellular (intrinsic) such as DNA damage or oxidative stress, or extracellular
(extrinsic) such as the cytokine hormone called tumor necrosis factor. In contrast,
necrosis is a more passive cell death mechanism generally characterized by cell
swelling. Depending upon the cell type and the death signal, the apoptotic and
necrotic mechanisms can overlap. More recently it has become clear that PCD
can be subdivided into sub-types based on caspase dependence and other
criteria For example, “aponecrosis” is a necrotic-like PCD that does not require
caspases, and “paraptosis” is a form of PCD observed during development that
involves an alternative form of caspase. Autophagic cell death is also observed
during development, and is a form of PCD characterized by high levels of
autophagy. Autophagy is a “self-eating” mechanism in which intracellular
components are digested inside specialized membrane-bound organelles.
Normal Role of Programmed Cell Death in Tissue Maintenance
Highly regulated PCD plays an important role during normal development, such
as the sculpting of human brain structure and digits, and the elimination of nonfunctional cells in the developing and adult immune systems . PCD in the adult is
required for tissue homeostasis, elimination of pathogen-invaded cells, and
wound healing. Normal human tissue homeostasis is estimated to involve the
PCD of several billion cells per day.
Repression of Programmed Cell Death in Cancer Cells and Senescent Cells
Cancer incidence increases exponentially during aging, making aging the
greatest risk factor for cancer. PCD normally plays a critical role as an anticancer mechanism Genetic and biochemical abnormalities within a cell normally
trigger PCD, however, cancer cells have typically acquired mutations that allow
them to escape or repress apoptosis and survive. One common mechanism
observed is heat shock protein (hsp) “addiction,” wherein cancer cells survive
due to dramatically up-regulated hsp expression that inhibits PCD pathways, for
example, by inhibiting the activity of the key apoptosis regulator p53 . Most
chemotherapies, including ionizing radiation, function by hyper-stimulating and
activating these otherwise repressed PCD pathways. In addition to apoptosis,
another critical anti-cancer mechanism is cellular senescence. Cellular
senescence is an irreversible cell cycle arrest that can result from telomere
erosion, oncogene activation, chromatin abnormalities and other types of
damage. Increasing evidence suggests that senescent cells accumulate during
aging and contribute to aging-related loss of function in various adult tissues.
This accumulation may result from the fact that senescent cells are resistant to
apoptosis due to repressed activity of PCD pathway components such as
caspase 3 and cell cycle factors that function in both cell division and apoptosis.
p53 is a Key Player in Programmed Cell Death and Life Span Regulation
The famous tumor-suppressor p53 is mutated in the majority of human cancers,
and it suggested that most of the other cancers have mutations in genes in the
p53 pathway that result in lack of normal p53 function; therefore loss of normal
p53 function appears to be a requirement for most cancers. p53 functions to
suppress cancer through at least two mechanisms: in response to cellular
damage and/or abnormal signaling, p53 causes cells to enter either apoptosis or
senescence, depending upon the signal and the cellular context). Either way,
further cell division is halted, thereby preventing that cell from becoming
cancerous. p53 has also been found to regulate life span in several species. For
example, in mouse, abnormal p53 activity can cause a premature aging-like
phenotype, associated with the accumulation of abnormal cells. In both
Drosophila and C. elegans, p53 function appears to limit life span, as mutation of
the endogenous p53 gene or expression of dominant-negative forms of p53
produces long-lived animals In C. elegans the increased life span of p53 mutants
and several other long-lived mutants appears to be dependent upon increased
autophagy Intriguingly, in Drosophila, p53 has been found to have both positive
and negative effects on adult life span, depending upon the particular tissue and
whether the animal is male or female, supporting a link between sexual
differentiation, PCD, and aging Because p53 is able to regulate PCD, cell
senescence, autophagy, mitochondrial metabolism, and other critical cell
processes determining how p53 and autophagy are affecting life span will be an
important area for future research.
The Role of Programmed Cell Death in Neurodegenerative Diseases
Aging-related neurodegenerative diseases such as Alzheimer’s disease,
Parkinson’s disease, and Huntington’s disease involve the accumulation of
abnormal protein deposits. Increased PCD has been observed for each disease,
where it appears to be counterproductive in that cells die that might otherwise
continue to support function of the tissue (Autophagy is normally involved in the
clearance of intracellular inclusions, including protein aggregates, and the
increased PCD observed in these diseases is typically autophagic cell death.
Increased Apoptosis in Tissues of Old Animals
An increased incidence of apoptosis has been reported for several tissues during
aging, even in the absence of overt aging-related disease. For example, aging-
associated atrophy of muscle, called sarcopenia in mammals, is observed in
organisms ranging from invertebrates to humans. Detailed analysis of sarcopenia
in rodents indicates an apoptotic-like mechanism, characterized by mitochondrial
changes and caspase-independence During aging in Drosophila, apoptotic-like
events are observed in both muscle and fat tissue, as indicated by DNA
fragmentation assay and caspase activation).
Role of Programmed Cell Death in Life Span Regulation
Because normally regulated PCD is required for tissue homeostasis, it seems
likely this process will be required for optimal life span, particularly in species like
mammals with abundant adult cell turnover. In contrast, the ectopic and
counterproductive apoptosis associated with tissues that incur damage during
aging, such as in sarcopenia, might be expected to limit life span. In C. elegans,
where adult somatic cells are all postmitotic, mutation of key conserved
apoptosis regulators such as the caspase gene ced-3 did not affect life span
Similarly, in Drosophila, over-expression of powerful caspase inhibitors such as
baculovirus p35 and DIAP1 in the adult animal had no detectable effect on life
span suggesting that, at least in the invertebrates, life span is not limited by a
canonical caspase-dependent apoptosis pathway. However, it remains possible
that life span might be limited by caspase-independent PCD mechanisms,
perhaps including the apoptotic-like events associated with muscle atrophy, and
this will be an interesting area for future research. Even the cell death observed
in aging yeast cells has several characteristics indicative of PCD In mammals,
investigating the role of PCD pathway genes in life span is complicated by the
normal requirement for PCD in development and adult tissue homeostasis, but in
the future, the targeting of PCD inhibition to specific tissues in the adult may yield
answers to the question of whether one or more PCD pathways function in
regulating mammalian life span.