Homeostasis
of multicellular organisms is controlled not only by the
proliferation and differentiation of cells, but also by
cell death. The death of cells during embryogenesis, metamorphosis,
endocrine-dependent tissue atrophy, a variety of pathologic
conditions, and normal tissue turnover, is called programmed
cell death (PCD). Most of PCD proceeds by apoptosis, a
process that includes condensation and segmentation of
nuclei, condensation and fragmentation of the cytoplasm,
and often extensive fragmentation of chromosomal DNA into
nucleosome units. Many cells can be activated to undergo
apoptosis following the interaction of selected ligands
with cell surface receptors. The most well studied receptors
are CD95/Fas/Apo1 (apoptosis inducing protein 1) and tumor
necrosis factor receptor 1 (TNFR1). Apoptosis mediated
by both signaling cascades result in activation of a family
of cystein proteases known as Caspases. However, Fas-mediated
death occurs much more rapidly than that triggered by the
TNFR1. Engagement of Fas by its ligand (Fas ligand, FasL,
CD95L), or by an appropriate antibody, results in the rapid
induction of PCD in susceptible cell lines. This process
bypasses the usual long sequence of signaling enzymes and
immediately activates preexisting Caspases. The action
of Fas is mediated via FADD (Fas-associated death domain)/
MORT1, an adapter protein that has a death domain at its
C-terminus and binds to the cytoplasmic death domain of
Fas. Human CD95/Fas/Apo1 antigen is a single transmembrane
glycoprotein receptor of 325 amino acids (45-48 kDa). Primary
sequence analysis of the extracellular portion of CD95/Fas/Apo-1
has revealed strong homologies with the extracellular domain
of receptors belonging to the TNF receptor family, which
includes TNF receptor types 1 and 2 (TNFR1/2), the low
affinity nerve growth factor receptor, and lymphocyte receptors
such as CD27, CD30, CD40, and OX40. An integral membrane
protein, with strong homology to TNF alpha and beta, has
been identified as Fas ligand.
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