Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.61 (caspase-8)
 6,833 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Galectin (Gal)-3, a M(r) 31000 member of the beta-galactoside-binding protein family, is a multifunctional protein implicated in a variety of biological functions, including tumor cell adhesion, proliferation, differentiation, angiogenesis, apoptosis, cancer progression, and metastasis. Here, we report that secreted extracellular Gal-3 can signal apoptosis of human T leukemia cell lines, human peripheral blood mononuclear cells, and activated mouse T cells after binding to cell surface glycoconjugate receptors through carbohydrate-dependent interactions because the apoptotic effect was found to be inhibited by lactose, specific sugar inhibitor, and to be dose dependent. However, the apoptosis sensitivity to Gal-3 varied among the different cell lines tested. We report that Gal-3-null Jurkat, CEM, and MOLT-4 cells were significantly more sensitive to exogenous Gal-3 than SKW6.4 and H9 cells, which express Gal-3, suggesting a cross-talk between the antiapoptotic activity of intracellular Gal-3 and proapoptotic activity of extracellular Gal-3. Furthermore, Gal-3-transfected CEM cells were found to be more resistant to C(2)-ceramide-induced apoptosis than the control CEM cells. Identification of Gal-3 cell surface receptors revealed that Gal-3 binding to CD7 and CD29 (beta(1) integrin) induced apoptosis. Gal-3 binding to its cell surface receptors results in activation of mitochondrial apoptosis events including cytochrome c release and caspase-3 activation, but not caspase-8 activation. Taken together, these results suggest that the induction of T-cell apoptosis by secreted Gal-3 may play a role in the immune escape mechanism during tumor progression through the induction of apoptosis to cancer-infiltrating T cells. The induction of T-cell apoptosis by secreted Gal-3 is dependent in part on the presence or absence of cytoplasmic Gal-3, providing a new insight for the immune escape mechanism of cancer cells.
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PMID:CD29 and CD7 mediate galectin-3-induced type II T-cell apoptosis. 1467 89

The major virulence factor of Cryptococcus neoformans is its capsular polysaccharide, which is also released into tissues. The shed polysaccharide is composed of glucuronoxylomannan, galactoxylomannan (GalXM), and mannoproteins. In a previous study, we demonstrated a direct interaction of purified soluble GalXM with T cells that induced their apoptosis. In this study, we focus on the mechanisms involved in the apoptotic effect of GalXM. In our experimental system, we analyzed the effect of GalXM on purified human T cells and Jurkat cells, a T cell line routinely used for apoptotic studies. Our results reveal that GalXM activates the extrinsic and intrinsic apoptotic pathways through the cleavage and recruitment of caspase-8. Caspase-8 elicits the downstream executioner caspase-3, caspase-6, and caspase-7 both directly and indirectly, via Bid cleavage and caspase-9 activation. These effects appeared to be primarily mediated by the interaction of GalXM with the glycoreceptors, which differed in human T and Jurkat cells. CD45 was primarily involved in Jurkat cells apoptosis while CD7 and CD43 mediated human T cell apoptosis. Our results highlight a new mechanism by which a microbial product can contribute to virulence through direct interaction with T cell glycoreceptors, thereby triggering lymphocyte apoptosis.
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PMID:Involvement of glycoreceptors in galactoxylomannan-induced T cell death. 1941 51

Galectin-1 (G1) and galectin-3 (G3) are carbohydrate-binding proteins that can signal apoptosis in T cells. We recently reported that a synthetic tetramer with two G1 and two G3 domains ("G1/G3 Zipper") induces Jurkat T cell death more potently than G1. The pro-apoptotic signaling pathway of G1/G3 Zipper was not elucidated, but we hypothesized based on prior work that the G1 domains acted as the signaling units, while the G3 domains served as anchors that increase glycan-binding affinity. To test this, here we studied the involvement of different cell membrane glycoproteins and intracellular mediators in pro-apoptotic signaling via G1/G3 Zipper, G1, and G3. G1/G3 Zipper induced Jurkat T cell death more potently than G1 and G3 alone or in combination. G1/G3 Zipper, G1, and G3 increased caspase-8 activity, yet only G1 and G3 depended on it to induce cell death. G3 increased caspase-3 activity more than G1/G3 Zipper and G1, while all three galectin variants required it to induce cell death. JNK activation had similar roles downstream of G1/G3 Zipper, G1, and G3, whereas ERK had differing roles. CD45 was essential for G1 activity, and was involved in signaling via G1/G3 Zipper and G3. CD7 inhibited G1/G3 Zipper activity at low galectin concentrations but not at high galectin concentrations. In contrast, CD7 was necessary for G1 and G3 signaling at low galectin concentration but antagonistic at high galectin concentrations. Collectively, these observations suggest that G1/G3 Zipper amplifies pro-apoptotic signaling through the integrated activity of both the G1 and G3 domains.
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PMID:A Synthetic Tetramer of Galectin-1 and Galectin-3 Amplifies Pro-apoptotic Signaling by Integrating the Activity of Both Galectins. 3199 89