MHC class II engagement inhibits CD99‐induced apoptosis and up‐regulation of T cell receptor and MHC molecules in human thymocytes and T cell line

Kim, Min Kyung; Choi, Yoon La; Kim, Seok Hyung; Choi, Eun Young; Park, Won Seo; Bae, Young-Soo; Woo, Sang Kyu; Park, Seong Hoe

doi:10.1016/s0014-5793(03)00567-2

Cited by 12 publications

(8 citation statements)

References 29 publications

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“…Overexpression was the result of their accelerated mobilization from cytosolic compartments to the plasma membrane. Whether or not these molecules are involved in mediating CD99 functions is still a matter of debate (Bernard et al, 1995;Hahn et al, 1997;Kasinrerk et al, 2000;Kim et al, 2003;Yoon et al, 2003). In ES, the engagement of CD99 resulted in cell aggregation and rapid externalization of PS, which is part of an apoptotic stimulus that induces ES cell death.…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanisms of CD99-induced caspase-independent cell death and cell–cell adhesion in Ewing's sarcoma cells: actin and zyxin as key intracellular mediators

et al. 2004

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CD99 is a unique 32-kDa cell surface molecule with broad cellular expression but still poorly understood biological functions. In cancer cells, CD99 is highly expressed in virtually all Ewing's sarcoma (ES). Engagement of CD99 induces fast homotypic aggregation of ES cells and caspaseindependent apoptosis. In this study, we analysed signal transduction after CD99 engagement on ES cells. Findings obtained with selective inhibitors indicated that only actin cytoskeleton integrity was essential for cell-cell adhesion and apoptosis of ES cells. Indeed, CD99 stimulation induced actin repolymerization, further supporting the role of cytoskeleton in CD99 signaling. Gene expression profiling of ES cells after CD99 engagement showed modulation in the expression of 32 genes. Among the pool of upregulated genes reported to be involved in cell adhesion, we chose to analyse the role of zyxin, a cytoplasmic adherens junction protein found to play a role in the regulation of the actin cytoskeleton. Overexpression of zyxin after CD99 ligation was confirmed by real-time PCR and Western blot. Treatment of ES cells with zyxin antisense oligonucleotides inhibited CD99-induced cell aggregation and apoptosis, suggesting a functional role for this protein. Therefore, our findings indicate that CD99 functions occur through reorganization of cytoskeleton and identify actin and zyxin as the early signaling events driven by CD99 engagement.

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Section: Discussionmentioning

confidence: 99%

Molecular mechanisms of CD99-induced caspase-independent cell death and cell–cell adhesion in Ewing's sarcoma cells: actin and zyxin as key intracellular mediators

et al. 2004

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“…The crucial biologic processes involving CD99 include lymphocyte development, cell adhesion and monocyte diapedesis, and expression of TCR, MHC class I and II as well as of some adhesion molecules (i.e., ELAM-1, VCAM-1, ICAM-1) by mobilization of these molecules from the Golgi to the plasma membrane (7)(8)(9)(10)(11)(12)(13)(14). In pathology, CD99 is found on the cell surface of EWS, acute lymphoblastic leukemia, thymic tumors, some spindle cell tumors (e.g., synovial sarcoma), hemangiopericytoma, meningioma, and malignant glioma, in which it confers high invasiveness and low survival rates (13,(15)(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

CD99 Triggering in Ewing Sarcoma Delivers a Lethal Signal through p53 Pathway Reactivation and Cooperates with Doxorubicin

Guerzoni

Fiori²,

Terracciano

et al. 2015

Clinical Cancer Research

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Purpose: The paucity of new drugs for the treatment of Ewing sarcoma (EWS) limits the cure of these patients. CD99 has a strong membranous expression in EWS cells and, being also necessary for tumor survival, is a suitable target to aim at. In this article, we described a novel human monospecific bivalent single-chain fragment variable diabody (dAbd C7) directed against CD99 of potential clinical application.Experimental Design: In vitro and in vivo evaluation of cell death and of the molecular mechanisms triggered by anti-CD99 agents were performed alone or in combination with doxorubicin to demonstrate efficacy and selectivity of the new dAbd C7.Results: The dAbd C7 induced rapid and massive EWS cell death through Mdm2 degradation and p53 reactivation. Mdm2 overexpression as well as silencing of p53 in p53wt EWS cells decreased CD99-induced EWS cell death, whereas treatment with nutlin-3 enhanced it. Furthermore, cell death was associated with induction of p21, bax, and mitochondrial depolarization together with substantial inhibition of tumor cell proliferation. Combined treatment of anti-CD99 dAbd C7 with doxorubicin was additive both in vitro and in vivo against EWS xenografts. Normal mesenchymal stem cells showed no p53 activation and were resistant to cell death, unless transformed by EWS-FLI, the oncogenic driver of EWS.Conclusions: These results indicate that dAbd C7 is a suitable candidate tool to target CD99 in patients with EWS able to spare normal stem cells from death as it needs an aberrant genetic context for the efficient delivery of CD99-triggered cell death.

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“…26 CD99 is involved in multiple cellular events such as E-rosetting for T lymphocytes, 27 T-cell adhesion, [28][29][30] apoptosis of immature thymocytes 31 and Ewing sarcoma cells in a caspaseindependent way, 32 up-regulation of T-cell receptor, 33 and major histocompatibility complex molecules. 34,35 The CD99 gene encodes 2 different proteins produced by alternative splicing, 36 the short form harboring a deletion in the cytoplasmic domain. Differential expression of these 2 forms is associated with distinct behaviors for phenomena such as CD99-induced cell adhesion or T-cell death.…”

Section: Introductionmentioning

confidence: 99%

CD99 expressed on human mobilized peripheral blood CD34+ cells is involved in transendothelial migration

Imbert

Belaaloui

Bardin

et al. 2006

Blood

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MHC class II engagement inhibits CD99‐induced apoptosis and up‐regulation of T cell receptor and MHC molecules in human thymocytes and T cell line

Cited by 12 publications

References 29 publications

Molecular mechanisms of CD99-induced caspase-independent cell death and cell–cell adhesion in Ewing's sarcoma cells: actin and zyxin as key intracellular mediators

Molecular mechanisms of CD99-induced caspase-independent cell death and cell–cell adhesion in Ewing's sarcoma cells: actin and zyxin as key intracellular mediators

CD99 Triggering in Ewing Sarcoma Delivers a Lethal Signal through p53 Pathway Reactivation and Cooperates with Doxorubicin

CD99 expressed on human mobilized peripheral blood CD34+ cells is involved in transendothelial migration

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