Transcription factors of the nuclear factor–κB/rel (NF-κB) family may be important in cell survival by regulating unidentified, anti-apoptotic genes. One such gene that protects cells from apoptosis induced by Fas or tumor necrosis factor type α (TNF), IEX- 1L, is described here. Its transcription induced by TNF was decreased in cells with defective NF-κB activation, rendering them sensitive to TNF-induced apoptosis, which was abolished by transfection with IEX- 1L. In support, overexpression of antisense IEX- 1L partially blocked TNF-induced expression of IEX -1L and sensitized normal cells to killing. This study demonstrates a key role of IEX- 1L in cellular resistance to TNF-induced apoptosis.
Members of the tumor necrosis factor receptor (TNFR) superfamily are important for cell growth and survival. In addition to providing costimulatory signals for cell proliferation, ligation of both TNFR1 and Fas can result in programmed cell death or apoptosis. The underlying mechanism requires an intact 80-aa stretch present in the cytoplasmic tails of both TNFR1 and Fas, termed the death domain (DD). Here we show that CD27, a member of the TNFR family, expressed on discrete subpopulations of T and B cells and known to provide costimulatory signals for T and B cell proliferation and B cell Ig production, can also induce apoptosis. Co-crosslinking of surface Ig receptors along with ligation of CD27 augments CD27-mediated apoptosis. Unlike TNFR1 and Fas, the cytoplasmic tail of CD27 is relatively short and lacks the DD. Using the yeast two-hybrid system, we have cloned a novel protein (Siva) that binds to the CD27 cytoplasmic tail. It has a DD homology region, a box-B-like ring finger, and a zinc finger-like domain. Overexpression of Siva in various cell lines induces apoptosis, suggesting an important role for Siva in the CD27-transduced apoptotic pathway.
The T-cell antigen CD28 provides a costimulatory signal that is required for T-cefl proliferation. (residues 191-194). Mutation of the Y191 within the motif resulted in a complete loss ofbinding, while mutation ofM194 caused partial loss of binding. Bding analysis showed that the CD28 Y(P)-MXM motif bound to the p85 C-and N-terminal SH2 domans with an afnity comparable to that observed for PDGF-R and insulin receptor substrate 1. In terms of snaling, CD28 ligation induced a dramatic increase in the recruitment and association of PI 3-kinase with the receptor. CD28 is likely to use PI 3-klipase as the second signal leading to T-cell proliferation, an event with implications for anergy and peripheral T-cell tolerance.Activation of the resting T lymphocyte involves at least two steps: an antigen-specific signal generated by the T-cell receptor (TcR)2/CD3 and CD4/CD8-p56lck complexes, followed by a second signal delivered by an accessory cell (1). The CD28 antigen predominates in providing the costimulatory signals for T-cell stimulation (ref. 2; for reviews see refs. 1 and 3). It contains a single immunoglobulin-like domain and a 51-amino acid cytoplasmic tail (4). B7-1 and related B7-2/ B70 are also members of the immunoglobulin supergene family and serve as ligands for CD28 (5-7). Suboptimal proliferation induced by antigen, anti-CD3 or anti-CD2 antibody is augmented by CD28 ligation (for review see ref. 8). Likewise, CD28 ligation by B7 serves as an obligatory second step in T-cell activation (for review see ref.3). CD28-transgenic mice exhibit profound defects in mitogenic responses (9). CD28 signaling stabilizes mRNA for various lymphokines, in particular interleukin 2 (reviewed in refs. 1 and 8). T-cell nonresponsiveness or anergy can be reversed by CD28 engagement (1-3, 10), an event of potential importance in the generation of cytolytic responses against tumors (11,12).An important question concerns the mechanism by which CD28 regulates T-cell growth and the manner in which the CD28 signaling pathway relates to signals generated by the TcRC/CD3-CD4 complex. CD4 and CD8 associate with the protein-tyrosine kinase p56lck, while TcRC/CD3 is cou- By contrast, intracellular events generated by CD28 differ from those induced by TcRC/CD3 ligation. CD28 signaling appears to occur independent of conventional phosphatidylinositol hydrolysis and the Ca2 -dependent cyclophilincalcineurin pathway and is resistant to cyclosporin and FK506 (3,8). CD28 signaling, however, is sensitive to inhibitors of tyrosine kinases and to coligation with the protein-tyrosine phosphatase CD45 (3,8). CD28 ligation in the presence of phorbol ester induced the tyrosine phosphorylation of proteins at 75 and 100 kDa (3,8). This potentially unique pathway leads to DNA binding activity at an element located in the 5' interleukin 2 enhancer region (for review see refs. 1 and 3). PI 3-kinase is a heterodimer consisting of an adaptor subunit (p85) with two SH2 domains that is coupled to a p110 catalytic subunit and is important to signali...
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