|[Frontiers in Bioscience 1, d12-18, January 1, 1996]|
SOLUBLE FAS/APO-1 SPLICING VARIANTS AND APOPTOSIS
Isabella Cascino, Giuliana Papoff, Adriana Eramo, and Giovina Ruberti
Department of Immunobiology, Institute of Cell Biology, National Research Council, Rome, Italy.
Received 12/01/95; Accepted 01/11/96; On-line 1/1/96
Development and homeostasis of multicellular organisms are controlled not only by cell proliferation and differentiation but also by the elimination of cells that are unnecessary or deleterious. This is achieved by a process referred to as programmed cell death or apoptosis (Reviewed in Ref. 1). Apoptosis leads to chromatin condensation and margination, nuclear fragmentation, cell shrinkage, membrane blebbing and in the majority, but not in all cells, enzymatic internucleosomal fragmentation of nuclear DNA (2,3).
Apoptosis is the result of an active cellular response that can be elicited by a variety of stimuli such as growth factor deprivation, a molecular damage that does not cause severe loss of integrity, or by triggering of specific cellular receptors such as the tumor necrosis factor receptor type 1 (TNFR1) or Fas/Apo-1. The Fas/Apo-1 molecule, also designated as CD95, (4,5) belongs to the TNFR family (6). Fas positive cells treated either with specific agonistic antibodies (7,8) or following interaction with the natural Fas ligand (FasL) (9-13) show the characteristic morphologic features of cells undergoing apoptosis (2,3).
Recent evidence suggests that dysregulation of apoptosis contributes to the pathogenesis of several human diseases including cancer, viral infections, autoimmune diseases, neurodegenerative disorders, and AIDS (Reviewed in Ref. 14).
In the immune system, Fas and FasL are involved in the down-regulation of immune reactions as well as in T cell mediated cytotoxicity. (Reviewed in Ref. 15). Spontaneous loss-of-function mutations of Fas and FasL have been identified respectively in lpr (16-20) and gld (12,13) mice. These mutations cause the accumulation of activated lymphocytes in tissues and accelerate the autoimmune disease processes. Fas gene mutations associated with T cell apoptosis defects have also been reported in children with a rare autoimmune lymphoproliferative syndrome (ALPS) (21,22).
There is growing evidence that not all Fas positive cells are susceptible to apoptosis induction. Several mechanisms of Fas-mediated apoptosis resistance have been postulated. These include a defective expression of hematopoietic cell protein tyrosine phosphatase (HCP) in lymphoid cells (23); high expression of FAP-1, a protein tyrosine phosphatase that associates with Fas (24); low expression of bax-alpha, a bcl-2 family member (25); mutations of the Fas gene in ALPS lymphocytes (21,22) and expression of a truncated Fas receptor lacking the intracellular death-signaling domain (FasExo8Del) in tumor resistant clones (26, 27).
In addition to the above mechanisms, it must be considered that Fas-mediated apoptosis undoubtedly involves a delicate balance of receptor/ligand interactions and that these may be modulated by soluble proteins. In fact there is accumulating evidence for the natural occurrence of soluble forms of cell surface receptors produced either by proteolytic cleavage of membrane-bound receptors or by alternative splicing. In this article, we summarize current knowledge on the human Fas splicing variants that have so far been reported (28-31). Next, we discuss the possible role of Fas soluble isoforms in the physiological and pathological fine tuning of apoptosis and consequently in the regulation of the immune responses.