Molecular Cloning of ADIR , a Novel Interferon Responsive Gene Encoding a Protein Related to the Torsins

Dron, Michel; Meritet, Jean François; Dandoy-Dron, Françoise; Meyniel, Jean-Philippe; Maury, Chantal; Tovey, Michaël G.

doi:10.1006/geno.2002.6709

Cited by 32 publications

(27 citation statements)

References 48 publications

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“…JNK2 and p38 MAPKs mediate IFN-γ production and Th1 cell differentiation, and inhibition of p38 MAPK in dnp38 transgenic mice results in decreased IFN-γ production by Th1 cells (15,36,37). ADIR encodes a protein involved in protein processing in the endoplasmic reticulum and contains a putative IFN-responsive ATP-binding site involved in regulating expression of genes critical for antigen presentation and immune surveillance against viruses and tumor cells (38). Our data, demonstrating decreased expression in the p38 MAPK pathway activator genes such as MINK, NFRKB, and PIK3CB, are in keeping with our hypothesis that the defects induced by the leukemic cells impair subsequent CD4 differentiation into Th1 cells.…”

Section: Discussionmentioning

confidence: 99%

Chronic lymphocytic leukemia cells induce changes in gene expression of CD4 and CD8 T cells

Görgün¹,

Holderried²,

Zahrieh³

et al. 2005

J. Clin. Invest.

261

163

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To examine the impact of tumors on the immune system, we compared global gene expression profiles of peripheral blood T cells from previously untreated patients with B cell chronic lymphocytic leukemia (CLL) with those from age-matched healthy donors. Although the cells analyzed were not part of the malignant clone, analysis revealed differentially expressed genes, mainly involved in cell differentiation in CD4 cells and defects in cytoskeleton formation, vesicle trafficking, and cytotoxicity in CD8 cells of the CLL patients. In coculture experiments using CLL cells and T cells from healthy allogeneic donors, similar defects developed in both CD4 and CD8 cells. These changes were induced only with direct contact and were not cytokine mediated. Identification of the specific pathways perturbed in the T cells of cancer-bearing patients will allow us to assess steps to repair these defects, which will likely be required to enhance antitumor immunity.

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Section: Discussionmentioning

confidence: 99%

Chronic lymphocytic leukemia cells induce changes in gene expression of CD4 and CD8 T cells

Görgün¹,

Holderried²,

Zahrieh³

et al. 2005

J. Clin. Invest.

261

163

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“…A basic local alignment sequence tool (BLAST) search of sequence SVAPALALFPA against a 6-frame translation of the European Molecular Biology Laboratory (EMBL) nucleotide database revealed 100% identity to amino acids 13 to 23 from an alternative open reading frame (ORF) of the ADIR gene, also known as TOR3A 37 Figure 2A). Both peptides were synthesized and loaded on T2 cells.…”

Section: Identification Of a Polymorphic Gene Responsible For Rdr2 Rementioning

confidence: 99%

“…37 This gene was found to be highly expressed in the MM cells, in other hematopoietic tumors, as well as nonhematopoietic tumor cell lines. Recognition of normal nonmalignant cells appears to be minor under steady state conditions, but activation of the target cell populations resulted in enhanced recognition by the CTL clone.…”

Section: Introductionmentioning

confidence: 99%

Multiple myeloma–reactive T cells recognize an activation-induced minor histocompatibility antigen encoded by the ATP-dependent interferon-responsive (ADIR) gene

Bergen

Kester

Jedema

et al. 2007

Blood

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Minor histocompatibility antigens (mHags) play an important role in both graft-versustumor effects and graft-versus-host disease (GVHD) after allogeneic stem cell transplantation. We applied biochemical techniques and mass spectrometry to identify the peptide recognized by a dominant tumor-reactive donor T-cell reactivity isolated from a patient with relapsed multiple myeloma who underwent transplantation and entered complete remission after donor lymphocyte infu- IntroductionAllogeneic stem cell transplantation (SCT) is a curative treatment in patients with hematologic cancers. In addition to the antitumor effects of chemotherapy, antibody treatment and/or irradiation administered as the conditioning regimen prior to transplantation, an allogeneic graft-versus-tumor (GVT) immunoreactivity significantly contributes to the curative potential of this therapy. [1][2][3][4][5] This GVT reactivity following HLA-matched SCT has been demonstrated to be mediated primarily by T cells from the donor. All reactive T cells from donor origin may not only mediate the beneficial GVT effect but are also responsible for the development of graft-versus-host disease (GVHD), which is the major detrimental complication after allogeneic SCT. 6,7 T-cell depletion of the stem cell graft removes both GVHD and GVT effect. [8][9][10] The antitumor reactivity can be reintroduced in case of persistent or relapsed hematologic malignancies after transplantation by donor lymphocyte infusion (DLI). [11][12][13][14][15] Whereas profound antitumor effects are frequently associated with GVHD in patients responding to DLI, postponed administration of DLI has been associated with a decreased risk of severe GVHD, and clinical observations indicate that more subtle antitumor reactivities can also be observed in the absence of GVHD. [16][17][18] The main targets of both GVHD and GVT reactivity after HLA-matched allogeneic SCT are minor histocompatibility antigens (mHags). [19][20][21] mHags are peptides differentially expressed by donor and recipient that can be recognized in the context of self-HLA molecules. mHags may arise from differential processing of peptides due to polymorphisms in the gene encoding the protein or by direct polymorphisms in the peptide sequence that is presented in the HLA molecules. 22,23 The clinical manifestation of immune responses against mHags is likely to be determined by the specific tissue expression of the proteins encoding these antigens. Whereas mHags constitutively expressed in many tissues are likely to be targets for combined alloreactive GVHD and GVT responses, T-cell responses directed against antigens that are restricted to the hematopoietic cell lineages including the malignant T cells of hematopoietic origin are likely to mediate a GVT reactivity without severe GVHD. 21,[24][25][26][27][28][29][30][31] However, antigens with variable expression in tissues may also be targets for relatively specific GVT responses because these proteins may not be expressed or recognized on normal tissues under steady state c...

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“…These proteins use ATP binding and hydrolysis to induce conformational changes in substrate molecules via a repetitive cycle of substrate binding and release; they tend to multimerize and typically unfold proteins or disassemble protein complexes (e.g., N-ethylmaleimide-sensitive factor; NSF) (5,6). The ⌬E302͞3-torsinA mutation lies within a C-terminal domain that is unique to a number of torsin-related proteins (8) but is not part of the AAA domain ( Fig. 1 A).…”

mentioning

confidence: 99%

Mislocalization to the nuclear envelope: An effect of the dystonia-causing torsinA mutation

Goodchild

Dauer

2004

Proc. Natl. Acad. Sci. U.S.A.

260

272

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Primary dystonia is a disease characterized by involuntary twisting movements caused by CNS dysfunction without underlying histopathology. DYT1 dystonia is a form of primary dystonia caused by an in-frame GAG deletion (⌬E302͞3) in the TOR1A gene that encodes the endoplasmic reticulum luminal protein torsinA. We show that torsinA is also present in the nuclear envelope (NE), where it appears to interact with substrate, and that the ⌬E302͞3 mutation causes a striking redistribution of torsinA from the endoplasmic reticulum to the NE. In addition, ⌬E302͞3-torsinA recruits WT torsinA to the NE, potentially providing insight into an understanding of the dominant inheritance of the disease. DYT1 dystonia appears to be a previously uncharacterized NE disease and the first, to our knowledge, to selectively affect CNS function. DYT1 dystonia is a childhood-onset CNS disorder characterized by dramatic motor dysfunction due to abnormal interneuronal signaling rather than neurodegeneration (1, 2). Therefore, understanding the molecular determinants of this disease might shed light on basic mechanisms that regulate neuronal function and plasticity.TorsinA is a widely expressed member of the AAA (ATPase associated with different cellular activities) protein family (3) (Fig. 1A). AAA proteins participate in a diverse range of biological functions, including membrane trafficking, powering cellular motors, organelle biogenesis, and protein chaperone activities (4-7). These proteins use ATP binding and hydrolysis to induce conformational changes in substrate molecules via a repetitive cycle of substrate binding and release; they tend to multimerize and typically unfold proteins or disassemble protein complexes (e.g., N-ethylmaleimide-sensitive factor; NSF) (5, 6). The ⌬E302͞3-torsinA mutation lies within a C-terminal domain that is unique to a number of torsin-related proteins (8) but is not part of the AAA domain ( Fig. 1 A). Biochemical and cellular studies of torsinA in overexpressing cellular systems suggest that the ⌬E302͞3 mutation does not alter the stability or solubility of torsinA or its ability to multimerize (9, 10).To elucidate the molecular mechanisms of primary dystonia, we examined the effect of the ⌬E302͞3 mutation on the behavior of torsinA. We find that the ⌬E302͞3 mutation causes torsinA to relocalize from the endoplasmic reticulum (ER) to the nuclear envelope (NE) in both patient tissue and neurons from ⌬E302͞3-torsinA transgenic mice. Further, we show that diseaseassociated torsinA recruits WT protein to the NE. Additional experiments suggest that torsinA is normally present in the NE, where it appears to interact with substrate(s). Materials and Methods TorsinA cDNA Plasmid Construction and Generation of TransgenicMice. Human torsinA cDNA was cloned into pcDNA3.1 (Invitrogen). Mutations were introduced by using QuikChange (Stratagene). Enhanced GFP (Clontech) was cloned into an NheI site introduced between residues 21 and 22 of torsinA [immediately following the N-terminal signal sequence cleavage site (11)...

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Molecular Cloning of ADIR , a Novel Interferon Responsive Gene Encoding a Protein Related to the Torsins

Cited by 32 publications

References 48 publications

Chronic lymphocytic leukemia cells induce changes in gene expression of CD4 and CD8 T cells

Chronic lymphocytic leukemia cells induce changes in gene expression of CD4 and CD8 T cells

Multiple myeloma–reactive T cells recognize an activation-induced minor histocompatibility antigen encoded by the ATP-dependent interferon-responsive (ADIR) gene

Mislocalization to the nuclear envelope: An effect of the dystonia-causing torsinA mutation

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