Platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) acts as a regulator of B-cell development, B-cell antigen receptor (BCR)–mediated activation, and autoimmune disease
Open Access
- 1 July 2002
- journal article
- Published by American Society of Hematology in Blood
- Vol. 100 (1), 184-193
- https://doi.org/10.1182/blood-2002-01-0027
Abstract
Second mitochondria-derived activator of caspases (Smac)/DIABLO is a mitochondrial protein that is released into the cytosol along with cytochrome c (cyt c) during the execution of the intrinsic pathway of apoptosis. Smac/DIABLO promotes apoptosis by neutralizing the inhibitory effect of the inhibitor of apoptosis (IAP) family of proteins on the processing and activities of the effector caspases. Present studies demonstrate that, upon engagement of the mitochondrial pathway of apoptosis, epothilone (Epo) B derivative BMS 247550, a novel nontaxane antimicrotubule agent, as well as the death ligand Apo-2L/TRAIL (tumor necrosis factor-α–related apoptosis-inducing ligand) induce the mitochondrial release and cytosolic accumulation of Smac/DIABLO, along with cyt c, in human acute leukemia Jurkat T cells. While it had no activity alone, ectopic overexpression of Smac/DIABLO or treatment with the N-terminus heptapeptide (Smac-7) or tetrapeptide (Smac-4) of Smac/DIABLO significantly increased Epo B– or Apo-2L/TRAIL–induced processing and PARP cleavage activity of caspase-3. This produced a significant increase in apoptosis of Jurkat cells (P < .05). Increased apoptosis was also associated with the down-regulation of XIAP, cIAP1, and survivin. Along with the increased activity of caspase-3, ectopic overexpression of Smac/DIABLO or cotreatment with Smac-4 also increased Epo B– or Apo-2L/TRAIL–induced processing of caspase-8 and Bid, resulting in enhanced cytosolic accumulation of cyt c. This was not due to increased assembly and activity of Apo-2L/TRAIL–induced DISC (death-inducing signaling complex) but dependent on the feedback activity of caspase-3. These findings demonstrate that cotreatment with the N-terminus Smac/DIABLO peptide is an effective strategy to enhance apoptosis triggered by the death receptor or mitochondrial pathway and may improve the antitumor activity of Apo-2L/TRAIL and Epo B.This publication has 42 references indexed in Scilit:
- Inhibition of antigen-receptor signaling by Platelet Endothelial Cell Adhesion Molecule-1 (CD31) requires functional ITIMs, SHP-2, and p56lckBlood, 2001
- The Human PECAM1 Gene Maps to 17q23Genomics, 1996
- The fate of self-reactive B cells depends primarily on the degree of antigen receptor engagement and availability of T cell help.The Journal of Experimental Medicine, 1996
- Disruption of the Cr2 Locus Results in a Reduction in B-1a Cells and in an Impaired B Cell Response to T-Dependent AntigenImmunity, 1996
- CD22 associates with protein tyrosine phosphatase 1C, Syk, and phospholipase C-gamma(1) upon B cell activation.The Journal of Experimental Medicine, 1996
- Augmented humoral and anaphylactic responses in FcγRII-deficient miceNature, 1996
- Defective B cell development and function in Btk-deficient miceImmunity, 1995
- A 13-amino-acid motif in the cytoplasmic domain of FcγRIIB modulates B-cell receptor signallingNature, 1994
- Origin of Murine B Cell LineagesAnnual Review of Immunology, 1993
- B-cell toleranceCurrent Opinion in Immunology, 1992