CD99 isoform expression dictates T‐cell functional outcomes

Alberti, Isabelle; Bernard, Ghislaine; Rouquette-Jazdanian, Alexandre K.; Pelassy, Claudette; Pourtein, Monique; Aussel, Claude; Bernard, Alain

doi:10.1096/fj.02-0049fje

Cited by 67 publications

(89 citation statements)

References 32 publications

(34 reference statements)

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“…In lymphocytes, CD99 can be expressed either as the full-length unspliced form (CD99wt) or as the short variant resulting from alternative splicing (CD99sh). Moreover, the differential expression dictates different functions (Hahn et al, 1997;Alberti et al, 2002;Jung et al, 2002). Although limited information is available with respect to this, the general idea is that both isoforms serve a functional role in the immune system.…”

Section: Discussionmentioning

confidence: 99%

“…CD99 is a transmembrane glycoprotein with no homology with other known proteins except for the Xga protein (Fouchet and Gane, 2000) that has been implicated in cell adhesion, apoptosis, differentiation of T cells and thymocytes (Bernard et al, 1997;Alberti et al, 2002), migration of monocytes (Schenkel et al, 2002) and intercellular adhesion between lymphocytes and endothelial cells (Bernard et al, 2000). In pathological conditions, the triggering of CD99 results in the induction of cell-cell adhesion and apoptosis of Ewing's sarcoma cells (Sohn et al, 1998;Scotlandi et al, 2000;Cerisano et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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CD99 isoforms dictate opposite functions in tumour malignancy and metastases by activating or repressing c-Src kinase activity

et al. 2007

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CD99 gene encodes two distinct proteins, produced by alternative splicing of CD99 gene transcript. Full-length CD99 isoform (CD99wt) is formed by an extracellular domain, followed by a transmembrane domain and a 36 amino-acid intracytoplasmic domain, which is partially deleted in the truncated, short form (CD99sh). A differential expression of these two CD99 molecules can lead to distinct functional outcomes in lymphocytes. To investigate the functional effects of CD99 molecules on malignancy, forced overexpression of the two CD99 isoforms was induced in osteosarcoma and prostate cancer cells. The two isoforms exhibited opposite functions: the major form dramatically inhibits anchorage-independent growth, anoikis resistance, migration and metastasis, whereas the CD99sh remarkably favours the phenomena. A mechanistic analysis of CD99-transfected osteosarcoma cells points to involvement of c-Src family kinase activity in regulating CD99 functions in malignancy. Ser168 residue of CD99 plays a pivotal role in the reversion of the malignant phenotype. Our findings highlight the involvement of CD99 in crucial processes of cancer malignancy, serving as a curtain raiser for this, so far neglected molecule. In addition, a dualistic role for the two CD99 isoforms was shown in agreement with what was observed for other cell adhesion molecules.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

CD99 isoforms dictate opposite functions in tumour malignancy and metastases by activating or repressing c-Src kinase activity

et al. 2007

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“…In the B lymphoblastoid cell line IM-9, the short-isoform which lacks the cytoplasmic domain, has been demonstrated to act antagonistically to the major long-isoform in the induction of cellular adhesion (Hahn et al, 1997). In addition, expression of the major form in a CD99-deficient Jurkat T cell line was sufficient to promote cell adhesion, whereas coexpression of the two isoforms was required to trigger T-cell death (Alberti et al, 2002). The diversity of biological responses to antibody-ligation of CD99 in the absence of mechanistic insights into CD99 function and the lack of rodent homologues that might be knocked-out for genetic studies prompted us to investigate the role of CD99 in ESFT by an RNAinterference approach.…”

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confidence: 99%

Suppression of KCMF1 by constitutive high CD99 expression is involved in the migratory ability of Ewing's sarcoma cells

et al. 2005

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High CD99 expression levels and rearrangements of the EWS gene with ETS transcription factor genes characterize the Ewing's sarcoma family of tumors (ESFT). CD99 is a cell surface glycoprotein whose engagement has been implicated in cell proliferation as well as upregulation and transport of several transmembrane proteins in hematopoietic cells. In ESFT, antibody ligation of CD99 induces fast homotypic cell aggregation and cell death although its functional role in these processes remains largely unknown. Here, using an RNAi approach, we studied for the first time the consequences of modulated CD99 expression in six different ESFT cell lines, representing the most frequent variant forms of EWS gene rearrangement. CD99 suppression resulted in growth inhibition and reduced migration of ESFT cells. Among genes whose expression changes in response to CD99 modulation, the potassium-channel modulatory factor KCMF1 was consistently upregulated. In a series of 22 primary ESFT, KCMF1 expression levels inversely correlated with CD99 abundancy. Cells forced to express ectopic KCMF1 showed a similar reduction in migratory ability as CD99 silenced ESFT cells. Our results suggest that in ESFT, high CD99 expression levels contribute to the malignant properties of ESFT by promoting growth and migration of tumor cells and identify KCMF1 as a potential metastasis suppressor gene downregulated by high constitutive CD99 expression in ESFT.

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“…Modification in the isomorphism of CD99 has been shown to occur, in particular, during differentiation of thymocytes [44]. Furthermore, the expression of the CD99 isoforms correlated perfectly with that of CD1a in human thymocytes; double positive human thymocytes express CD1a and the two forms of CD99, while the single positive thymocytes that have lost expression of CD1a only expressed the long form of CD99 (Supporting Information Fig.…”

Section: Discussionmentioning

confidence: 88%

“…We confirmed this observation in CD99LF-Jurkat cells silenced for CD99, were the phosphorylation of ATF-2 and CREB-1 was decreased. Silencing CD99 in human iDCs allows us to confirm that the mechanism described in Jurkat cell line also occurred in primary cells.Modification in the isomorphism of CD99 has been shown to occur, in particular, during differentiation of thymocytes [44]. Furthermore, the expression of the CD99 isoforms correlated perfectly with that of CD1a in human thymocytes; double positive human thymocytes express CD1a and the two forms of CD99, while the single positive thymocytes that have lost expression of CD1a only expressed the long form of CD99 (Supporting Information Fig.…”

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confidence: 88%

CD99 isoforms regulate CD1a expression in human monocyte‐derived DCs through ATF‐2/CREB‐1 phosphorylation

et al. 2016

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CD1a expression is considered one of the major characteristics qualifying in vitro human dendritic cells (DCs) during their generation process. Here, we report that CD1A transcription is regulated by a mechanism involving the long and short isoforms of CD99. Using a lentiviral construct encoding for a CD99 short hairpin RNA, we were able to inhibit CD99 expression in human primary DCs. In such cells, CD1a membrane expression increased and CD1A transcripts were much higher in abundance compared to cells expressing CD99 long form (CD99LF). We also show that CD1A transcription is accompanied by a switch in expression from CD99LF to expression at comparable levels of both CD99 isoforms during immature DCs generation in vitro. We demonstrate that CD99LF maintains a lower level of CD1A transcription by up-regulating the phosphorylated form of the ATF-2 transcription factor and that CD99 short form (SF) is required to counteract this regulatory mechanism. Elucidation of the molecular mechanisms related to CD99 alternative splicing will be very helpful to better understand the transcriptional regulatory mechanism of CD1a molecules during DCs differentiation and its involvement in the immune response.Keywords: alternative splicing-ATF2-CREB1 r CD99 r Dendritic cells r Nonclassical MHC Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionPresentation of foreign antigens in the form of proteins or lipids solicits specialized molecular complexes carried by dendritic cells (DCs). The molecules of the classical and nonclassical major Correspondence: Dr. Ghislaine Bernard e-mail: bernardg@unice.fr histocompatibility complex (MHC) class I present antigens to T cells and these two families of molecules have very similar structures [1][2][3].Among the nonclassical MHC molecules is the CD1 family of molecules that assures the presentation of lipid and glycolipid † Deceased C 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2016. 46: 1460-1471 Immunomodulation 1461 antigens [4,5]. This family consists of five genes, including CD1A, B, C, D and E. The first four give rise to cell surface proteins CD1a, CD1b, CD1c, CD1d that are able to present the antigens, while the gene CD1E codes for the cytoplasmic protein CD1e [6][7][8]. CD1a is expressed on the membranes of thymocytes, dermal DCs and Langerhans cells, and allows distinction between subpopulations of DCs. No such equivalent has been reported in mice [8].CD1a is expressed during generation of DCs derived from monocytes when cultured in the presence of GMCSF and IL4 in vitro [9]. Two subpopulations of immature DCs (iDCs), i.e. CD1a high and CD1a low DCs, are produced in these conditions [10,11]. In addition to their phenotypic differences, these cells show functional differences, in particular in terms of secretion of cytokines. In contrast to CD1a high DCs, CD1a low DCs produce low amounts of IL12 but produce high amounts of IL10. This profile of cytokines impacts on the f...

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CD99 isoform expression dictates T‐cell functional outcomes

Cited by 67 publications

References 32 publications

CD99 isoforms dictate opposite functions in tumour malignancy and metastases by activating or repressing c-Src kinase activity

CD99 isoforms dictate opposite functions in tumour malignancy and metastases by activating or repressing c-Src kinase activity

Suppression of KCMF1 by constitutive high CD99 expression is involved in the migratory ability of Ewing's sarcoma cells

CD99 isoforms regulate CD1a expression in human monocyte‐derived DCs through ATF‐2/CREB‐1 phosphorylation

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