of which originate from a single fertilized egg. If this first cell divides
into 2, the progeny cells into 4, and so on, it would take only about 45
rounds of division to produce the number of cells required to make an
adult human. In fact, cell division occurs constantly through our
lifetimes, such that we generate a new complete set of 3 10 13 cells
every 2 weeks. The reason that multicellular organisms do not become
infinitely large is because the proliferation of cells is balanced by cell
death.
Necrosis
In cells that are injured, ATP concentrations fall so low that the Na+/K+ ATPase can no longer
operate, and therefore
ion concentrations are no longer controlled. This causes the cells to swell and then burst. The
cell contents then leak
out, causing the surrounding tissues to become inflamed. Cells that die by suicide on the
other hand shrink, and their
cell contents are packaged into small membrane-bound packets called blebs. The nuclear
DNA becomes chopped up
into small fragments, each of which becomes enclosed in a portion of the nuclear envelope.
The dying cell modifies its
plasma membrane, signaling to macrophages, which respond by engulfing the blebs and the
remaining cell fragments .
*Three morphologic changes follow:
Coagulative necrosis.
A.Normal heart. All myocytes are nucleated, and
striations are clear.
B. Myocardial infarction. The heart from a patient
Following acute myocardial infarction. The necrotic cells
are deeply eosinophilic and most have lost their nuclei.
APOPTOSIS
BARE BEGINNINGS
*Spontaneous cell death as a physiological event was discussed almost as
soon as stains became available. It was born with a bang in 1885 in a paper
by the same Walther Flemming who created the terms chromatin and
mitosis. Flemming studied ovarian follicles in mammals and noticed that
the epithelial lining of regressing follicles was littered with cells the nuclei of
which were breaking up.
*Sydney Brenner's studies on animal development began in the late1950s in what was to become the Laboratory of Molecular Biology
(LMB) in Cambridge, UK. It was at this lab that during the 1970s and
1980s, a team led by John Sulston succeeded in tracing the nematode
Caenorhabditis elegans entire embryonic cell lineage. In other words,
Sulston and his team had traced where each and every cell in the
roundworm's embryo came from during the division process, and where
it ended up.
Apoptosis actually
Whats in a name?
The term, Apoptosis was coined in 1972 by Kerr, Wyllie and Currie in
their landmark article introducing the concept of Programmed cell death
titled, APOPTOSIS: A BASIC BIOLOGICAL PHENOMENON WITH
WIDE- RANGING IMPLICATIONS IN TISSUE KINETICS.
We are most grateful to Professor James Cormack of the Department of Greek,
University of Aberdeen, for suggesting this term. The word " apoptosis " is used
in Greek to describe "the dropping off " or " falling off " of petals from flowers,
or leaves from trees. To show the derivation clearly, we propose that the stress
should be on the penultimate syllable, the second half of the word being
pronounced like " ptosis " (with the " p " silent), which comes from the same
root " to fall and is already used to describe drooping of the upper eyelid.
A general mechanism of controlled cell deletion, which is complementary
to mitosis in the regulation of animal cell populations.
Apoptosis Produces
Individual Cell Death Amidst
Viable Cells
Stages
The earliest phase is the stimulus that provokes the apoptotic response. This may be
an external signal delivered through surface receptors or may originate inside the cell
from the action of a drug, toxin, or radiation.
The next phase includes detection of this signal or metabolic state and transduction of
the signal. Signal transduction pathways send this message to the cell death effector
machinery.
The effector phase is the third part of the cell death mechanism and includes the
proteases that are activated during apoptosis, as well as their positive and negative
regulators.
The fourth phase of cell death is the postmortem phase, in which the cell's chromatin
condenses and its DNA is degraded. In vivo (but not necessarily in vitro) dying cells are
recognized and engulfed by other cells.
Molecular mechanism
*Insight into the molecular basis of apoptosis was first revealed in studies on the
nematode
worm C. elegans, whose cells can be followed with absolute precision during
embryonic
development.
*Of the 1090 cells produced during the development of this worm,131 cells are
normally
destined to die by apoptosis yielding 959 somatic cells seen in adult worm .
(Sulston and Horvitz, 1977; Sulston et al., 1983).
* Nearly all dying cells undergo the same sequence
(Sulston and Horvitz, 1977; Sulston et al., 1983).
of morphological changes .
*A number of mutations affecting the process of cell death have been isolated.
These mutations,
which have defined the genes ced-7 (for cell death abnormal), ced-2, and nut-7
(nuclease
deficient) (Sulston, 1976; Hedgecock et al., 1983), affect all programmed cell deaths.
Thus, all cell deaths
appear to involve the same genetic (and, hence, molecular) processes.
Crucial Findings
*In 1986,Robert Horvitz and his colleagues at the Massachusetts
Institute of
Technology discovered that worms carrying a mutation in the CED-3
gene proceed
through development without losing any of their cells to apoptosis.
This finding
suggested that the product of the CED-3 gene played a crucial role in
the process of
apoptosis in this organism.
*Two genes, CED-3 and CED-4, were identified as genes required for
cell death:
Inactivating mutations in either of these two genes prevents all
developmentally
occurring cell deaths in C. elegans. This observation also provided
the first direct
evidence that cells die by an intrinsic suicide program.
*CED-3 is a protease, whereas CED-4 is a protein that activates CED3 by interacting
with it in dying cells. Another gene, CED-9,acts to protect cells from
Ghgm;;
References
*Cell and Molecular Biology- Gerard Karp.
*Apoptosis, Oncosis, and NecrosisGuido Majno and Isabelle Joris From the Department of Pathology, University of
Massachusetts Medical School, Worcester,
Massachusetts. American Journal of Pathology, Vol. 146, No. 1, January 1995 Copyright )
American Society for Investigative
Pathology.
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