{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T22:35:53Z","timestamp":1791326153544,"version":"4.3.1"},"reference-count":77,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2009,5,1]],"date-time":"2009-05-01T00:00:00Z","timestamp":1241136000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,5,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Killer lymphocytes recognize stress-activated NKG2D ligands on tumors. We examined NKG2D ligand expression in head and neck squamous cell carcinoma (HNSCC) cells and other cell lines. HNSCC cells typically expressed MHC class I chain-related gene A (MICA), MICB, UL16-binding protein (ULBP)2, and ULBP3, but they were uniformly negative for cell surface ULBP1 and ULBP4. We then studied how cancer treatments affected NKG2D ligand expression. NKG2D ligand expression was not changed by most cancer-relevant treatments. However, bortezomib and other proteasome inhibitor drugs with distinct mechanisms of action dramatically and specifically up-regulated HNSCC ULBP1 mRNA and cell surface protein. Proteasome inhibition also increased RNA for ULBP1 and other NKG2D ligands in nontransformed human keratinocytes. Proteasome inhibitor drugs increased ULBP1 transcription by acting at a site in the 522-bp ULBP1 promoter. Although the DNA damage response pathways mediated by ATM (ataxia-telangiectasia, mutated) and ATR (ATM and Rad3-related) signaling had been reported to up-regulate NKG2D ligand expression, we found that ULBP1 up-regulation was not inhibited by caffeine and wortmannin, inhibitors of ATM\/ATR signaling. ULBP1 expression in HNSCC cells was not increased by several ATM\/ATR activating treatments, including bleomycin, cisplatin, aphidicolin, and hydroxyurea. Ionizing radiation caused ATM activation in HNSCC cells, but high-level ULBP1 expression was not induced by gamma radiation or UV radiation. Thus, ATM\/ATR signaling was neither necessary nor sufficient for high-level ULBP1 expression in human HNSCC cell lines and could not account for the proteasome effect. The selective induction of ULBP1 expression by proteasome inhibitor drugs, along with variable NKG2D ligand expression by human tumor cells, indicates that NKG2D ligand genes are independently regulated.<\/jats:p>","DOI":"10.4049\/jimmunol.0801214","type":"journal-article","created":{"date-parts":[[2009,5,4]],"date-time":"2009-05-04T16:48:20Z","timestamp":1241455700000},"page":"6600-6609","source":"Crossref","is-referenced-by-count":60,"title":["Proteasome Regulation of\n                    <i>ULBP1<\/i>\n                    Transcription"],"prefix":"10.1093","volume":"182","author":[{"given":"James E","family":"Butler","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine"},{"name":"Department of Microbiology, Immunology, and Molecular Genetics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikel B","family":"Moore","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven R","family":"Presnell","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huei-Wei","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N Jan","family":"Chalupny","sequence":"additional","affiliation":[{"name":"Department of Oncology , Amgen, Seattle, WA 98101"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles T","family":"Lutz","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine"},{"name":"Department of Microbiology, Immunology, and Molecular Genetics"},{"name":"Markey Cancer Center, University of Kentucky , Lexington, KY 40536"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2009,5,15]]},"reference":[{"key":"2026012806301425700_R1","first-page":"1399","article-title":"Stress signals activate natural killer cells.","volume-title":"J. Exp. Med.","year":"2002"},{"key":"2026012806301425700_R2","first-page":"781","article-title":"Roles of the NKG2D immunoreceptor and its ligands.","volume-title":"Nat. Rev. Immunol.","year":"2003"},{"key":"2026012806301425700_R3","first-page":"469","article-title":"Stress management: MHC class I and class I-like molecules as reporters of cellular stress.","volume-title":"Immunity","year":"2003"},{"key":"2026012806301425700_R4","first-page":"167","article-title":"NKG2D-mediated activation of cytotoxic lymphocytes: unique signaling pathways and distinct functional outcomes.","volume-title":"Semin. Immunol.","year":"2006"},{"key":"2026012806301425700_R5","first-page":"571","article-title":"NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy.","volume-title":"Immunity","year":"2008"},{"key":"2026012806301425700_R6","first-page":"737","article-title":"Promiscuity and the single receptor: NKG2D.","volume-title":"Nat. Rev. Immunol.","year":"2007"},{"key":"2026012806301425700_R7","first-page":"439","article-title":"Regulation of ligands for the activating receptor NKG2D.","volume-title":"Immunology","year":"2007"},{"key":"2026012806301425700_R8","first-page":"e518","article-title":"In vivo expression pattern of MICA and MICB and its relevance to auto-immunity and cancer.","volume-title":"PLoS ONE","year":"2007"},{"key":"2026012806301425700_R9","first-page":"411","article-title":"Symmetry recognizing asymmetry: analysis of the interactions between the C-type lectin-like immunoreceptor NKG2D and MHC class I-like ligands.","volume-title":"Structure","year":"2003"},{"key":"2026012806301425700_R10","first-page":"159","article-title":"Regulation of NKG2D ligand gene expression.","volume-title":"Hum. Immunol.","year":"2006"},{"key":"2026012806301425700_R11","first-page":"11805","article-title":"NKG2D-independent suppression of T cell proliferation by H60 and MICA.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"2005"},{"key":"2026012806301425700_R12","first-page":"11521","article-title":"Ectopic expression of retinoic acid early inducible-1 gene (RAE-1) permits natural killer cell-mediated rejection of a MHC class I-bearing tumor in vivo.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"2001"},{"key":"2026012806301425700_R13","first-page":"165","article-title":"Rae1 and H60 ligands of the NKG2D receptor stimulate tumour immunity.","volume-title":"Nature","year":"2001"},{"key":"2026012806301425700_R14","first-page":"8996","article-title":"MICA\/NKG2D-mediated immunogene therapy of experimental gliomas.","volume-title":"Cancer Res.","year":"2003"},{"key":"2026012806301425700_R15","first-page":"1325","article-title":"NKG2D recognition and perforin effector function mediate effective cytokine immunotherapy of cancer.","volume-title":"J. Exp. Med.","year":"2004"},{"key":"2026012806301425700_R16","first-page":"734","article-title":"Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation.","volume-title":"Nature","year":"2002"},{"key":"2026012806301425700_R17","first-page":"1389","article-title":"Functional expression and release of ligands for the activating immunoreceptor NKG2D in leukemia.","volume-title":"Blood","year":"2003"},{"key":"2026012806301425700_R18","first-page":"7335","article-title":"Elevated TGF-\u03b21 secretion and down-modulation of NKG2D underlies impaired NK cytotoxicity in cancer patients.","volume-title":"J. Immunol.","year":"2004"},{"key":"2026012806301425700_R19","first-page":"928","article-title":"Sustained localized expression of ligand for the activating NKG2D receptor impairs natural cytotoxicity in vivo and reduces tumor immunosurveillance.","volume-title":"Nat. Immunol.","year":"2005"},{"key":"2026012806301425700_R20","first-page":"1495","article-title":"Loss of nonclassical MHC molecules MIC-A\/B expression during progression of uveal melanoma.","volume-title":"Br. J. Cancer","year":"2004"},{"key":"2026012806301425700_R21","first-page":"17","article-title":"Upregulation of MICA on high-grade invasive operable breast carcinoma.","volume-title":"Cancer Immun.","year":"2007"},{"key":"2026012806301425700_R22","first-page":"1076","article-title":"Role of NKG2D in tumor cell lysis mediated by human NK cells: cooperation with natural cytotoxicity receptors and capability of recognizing tumors of nonepithelial origin.","volume-title":"Eur. J. Immunol.","year":"2001"},{"key":"2026012806301425700_R23","first-page":"600","article-title":"Expression of stress-induced MHC class I related chain molecules on human melanoma.","volume-title":"J. Invest. Dermatol.","year":"2002"},{"key":"2026012806301425700_R24","first-page":"6178","article-title":"Major histocompatibility complex class I-related chain A and UL16-binding protein expression on tumor cell lines of different histotypes: analysis of tumor susceptibility to NKG2D-dependent natural killer cell cytotoxicity.","volume-title":"Cancer Res.","year":"2002"},{"key":"2026012806301425700_R25","first-page":"2033","article-title":"NKG2D engagement of colorectal cancer-specific T cells strengthens TCR-mediated antigen stimulation and elicits TCR independent anti-tumor activity.","volume-title":"Eur. J. Immunol.","year":"2003"},{"key":"2026012806301425700_R26","first-page":"2175","article-title":"Ovarian carcinoma expresses the NKG2D ligand Letal and promotes the survival and expansion of CD28\u2212 antitumor T cells.","volume-title":"Cancer Res.","year":"2004"},{"key":"2026012806301425700_R27","first-page":"320","article-title":"Lysis of a broad range of epithelial tumour cells by human \u03b3\u03b4 T cells: involvement of NKG2D ligands and T-cell receptor- versus NKG2D-dependent recognition.","volume-title":"Scand. J. Immunol.","year":"2007"},{"key":"2026012806301425700_R28","first-page":"769","article-title":"Chemoprevention of head and neck cancer.","volume-title":"Semin. Oncol.","year":"2004"},{"key":"2026012806301425700_R29","first-page":"43","article-title":"MICA and MICB overexpression in oral squamous cell carcinoma.","volume-title":"J. Oral Pathol. Med.","year":"2007"},{"key":"2026012806301425700_R30","first-page":"848","article-title":"Genes in the HLA region indicative for head and neck squamous cell carcinoma.","volume-title":"Mol. Immunol.","year":"2007"},{"key":"2026012806301425700_R31","first-page":"4023","article-title":"Interleukin 2 gene transfer prevents NKG2D suppression and enhances antitumor efficacy in combination with cisplatin for head and neck squamous cell cancer.","volume-title":"Cancer Res.","year":"2002"},{"key":"2026012806301425700_R32","first-page":"123","article-title":"ULBPs, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor.","volume-title":"Immunity","year":"2001"},{"key":"2026012806301425700_R33","first-page":"129","article-title":"ULBP4 is a novel ligand for human NKG2D.","volume-title":"Biochem. Biophys. Res. Commun.","year":"2003"},{"key":"2026012806301425700_R34","first-page":"5.7.1","article-title":"Analysis of cellular DNA content by flow cytometry. J. E. Coligan, Jr, and A. M. Kruisbeek, Jr, and D. H. Margulies, Jr, and E. M. Shevach, Jr, and W. Strober, Jr, eds.","volume-title":"Current Protocols in Immunology","year":"2004"},{"key":"2026012806301425700_R35","first-page":"5966","article-title":"Epigenetic control of highly homologous killer Ig-like receptor gene alleles.","volume-title":"J. Immunol.","year":"2005"},{"key":"2026012806301425700_R36","first-page":"1078","article-title":"Two human ULBP\/RAET1 molecules with transmembrane regions are ligands for NKG2D.","volume-title":"J. Immunol.","year":"2004"},{"key":"2026012806301425700_R37","first-page":"1221","article-title":"Functional redundancy of transcription factor-binding sites in the killer cell Ig-like receptor (KIR) gene promoter.","volume-title":"Int. Immunol.","year":"2006"},{"key":"2026012806301425700_R38","first-page":"248","article-title":"A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding.","volume-title":"Anal. Biochem.","year":"1976"},{"key":"2026012806301425700_R39","volume-title":"Molecular Cloning: A Laboratory Manual","year":"1989"},{"key":"2026012806301425700_R40","first-page":"2091","article-title":"Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer.","volume-title":"N. Engl. J. Med.","year":"2003"},{"key":"2026012806301425700_R41","first-page":"655","article-title":"Comparison of bleomycin and radiation in the G2 assay of chromatid breaks.","volume-title":"Int. J. Radiat. Biol.","year":"2003"},{"key":"2026012806301425700_R42","first-page":"245","article-title":"The ubiquitin-proteasome pathway and proteasome inhibitors.","volume-title":"Med. Res. Rev.","year":"2001"},{"key":"2026012806301425700_R43","first-page":"3520","article-title":"Direct and natural killer cell-mediated antitumor effects of low-dose bortezomib in hepatocellular carcinoma.","volume-title":"Clin. Cancer Res.","year":"2008"},{"key":"2026012806301425700_R44","first-page":"1546","article-title":"Selective induction of expression of a ligand for the NKG2D receptor by proteasome inhibitors.","volume-title":"Cancer Res.","year":"2008"},{"key":"2026012806301425700_R45","first-page":"7278","article-title":"Long-term exposure of the HT-29 human intestinal epithelial cell line to TNF causes sustained up-regulation of the polymeric Ig receptor and proinflammatory genes through transcriptional and posttranscriptional mechanisms.","volume-title":"J. Immunol.","year":"2005"},{"key":"2026012806301425700_R46","first-page":"30419","article-title":"Transcriptional regulation of ULBP1, a human ligand of the NKG2D receptor.","volume-title":"J. Biol. Chem.","year":"2006"},{"key":"2026012806301425700_R47","first-page":"1186","article-title":"The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor.","volume-title":"Nature","year":"2005"},{"key":"2026012806301425700_R48","first-page":"606","article-title":"Antigen-activated human T lymphocytes express cell-surface NKG2D ligands via an ATM\/ATR-dependent mechanism and become susceptible to autologous NK-cell lysis.","volume-title":"Blood","year":"2007"},{"key":"2026012806301425700_R49","first-page":"4375","article-title":"Inhibition of phosphoinositide 3-kinase related kinases by the radiosensitizing agent wortmannin.","volume-title":"Cancer Res.","year":"1998"},{"key":"2026012806301425700_R50","first-page":"889","article-title":"DNA damage-induced activation of ATM and ATM-dependent signaling pathways.","volume-title":"DNA Repair (Amst.)","year":"2004"},{"key":"2026012806301425700_R51","first-page":"499","article-title":"DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation.","volume-title":"Nature","year":"2003"},{"key":"2026012806301425700_R52","first-page":"5813","article-title":"Transcription factors activated in mammalian cells after clinically relevant doses of ionizing radiation.","volume-title":"Oncogene","year":"2003"},{"key":"2026012806301425700_R53","first-page":"152","article-title":"A role for ATR in the DNA damage-induced phosphorylation of p53.","volume-title":"Genes Dev.","year":"1999"},{"key":"2026012806301425700_R54","first-page":"1013","article-title":"The ATM\/p53 pathway is commonly targeted for inactivation in squamous cell carcinoma of the head and neck (SCCHN) by multiple molecular mechanisms.","volume-title":"Oral Oncol.","year":"2005"},{"key":"2026012806301425700_R55","first-page":"629","article-title":"The DNA damage response: sensing and signaling.","volume-title":"Curr. Opin. Cell Biol.","year":"2004"},{"key":"2026012806301425700_R56","first-page":"7596","article-title":"RNA interference targeting transforming growth factor-\u03b2 enhances NKG2D-mediated antiglioma immune response, inhibits glioma cell migration and invasiveness, and abrogates tumorigenicity in vivo.","volume-title":"Cancer Res.","year":"2004"},{"key":"2026012806301425700_R57","first-page":"L222","article-title":"NKG2D ligands are expressed on stressed human airway epithelial cells.","volume-title":"Am. J. Physiol.","year":"2006"},{"key":"2026012806301425700_R58","first-page":"6879","article-title":"Broad tumor-associated expression and recognition by tumor-derived \u03b3\u03b4 T cells of MICA and MICB.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"1999"},{"key":"2026012806301425700_R59","first-page":"1737","article-title":"Recognition of stress-induced MHC molecules by intestinal epithelial \u03b3\u03b4 T cells.","volume-title":"Science","year":"1998"},{"key":"2026012806301425700_R60","first-page":"3615","article-title":"Ligands for natural killer cell-activating receptors are expressed upon the maturation of normal myelomonocytic cells but at low levels in acute myeloid leukemias.","volume-title":"Blood","year":"2005"},{"key":"2026012806301425700_R61","first-page":"499","article-title":"Control of mRNA decay by heat shock-ubiquitin-proteasome pathway.","volume-title":"Science","year":"1999"},{"key":"2026012806301425700_R62","first-page":"287","article-title":"Posttranslational regulation of the NKG2D ligand Mult1 in response to cell stress.","volume-title":"J. Exp. Med.","year":"2009"},{"key":"2026012806301425700_R63","first-page":"1686","article-title":"Intrinsic sensor of oncogenic transformation induces a signal for innate immunosurveillance.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"2008"},{"key":"2026012806301425700_R64","first-page":"10","article-title":"Oxidative stress increases MICA and MICB gene expression in the human colon carcinoma cell line (CaCo-2).","volume-title":"Biochim. Biophys. Acta","year":"2001"},{"key":"2026012806301425700_R65","first-page":"474","article-title":"The switch from latent to productive infection in Epstein-Barr virus-infected B cells is associated with sensitization to NK cell killing.","volume-title":"J. Virol.","year":"2007"},{"key":"2026012806301425700_R66","first-page":"4611","article-title":"Role of NK cell-activating receptors and their ligands in the lysis of mononuclear phagocytes infected with an intracellular bacterium.","volume-title":"J. Immunol.","year":"2005"},{"key":"2026012806301425700_R67","first-page":"2357","article-title":"Cytokine and contact-dependent activation of natural killer cells by influenza A or Sendai virus-infected macrophages.","volume-title":"J. Gen. Virol.","year":"2004"},{"key":"2026012806301425700_R68","first-page":"1245","article-title":"NKG2D-mediated natural killer cell protection against cytomegalovirus is impaired by viral gp40 modulation of retinoic acid early inducible 1 gene molecules.","volume-title":"J. Exp. Med.","year":"2003"},{"key":"2026012806301425700_R69","first-page":"2001","article-title":"Cutting edge: Toll-like receptor signaling in macrophages induces ligands for the NKG2D receptor.","volume-title":"J. Immunol.","year":"2004"},{"key":"2026012806301425700_R70","first-page":"1530","article-title":"Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341.","volume-title":"Blood","year":"2003"},{"key":"2026012806301425700_R71","first-page":"5583","article-title":"NF-\u03baB regulates expression of the MHC class I-related chain A gene in activated T lymphocytes.","volume-title":"J. Immunol.","year":"2004"},{"key":"2026012806301425700_R72","first-page":"49","article-title":"Integrating cell-signalling pathways with NF-\u03baB and IKK function.","volume-title":"Nat. Rev. Mol. Cell Biol.","year":"2007"},{"key":"2026012806301425700_R73","first-page":"961","article-title":"Promoter region architecture and transcriptional regulation of the genes for the MHC class I-related chain A and B ligands of NKG2D.","volume-title":"J. Immunol.","year":"2007"},{"key":"2026012806301425700_R74","first-page":"802","article-title":"Inefficient proteasomal-degradation pathway stabilizes AP-2\u03b1 and activates HER-2\/neu gene in breast cancer.","volume-title":"Int. J. Cancer","year":"2006"},{"key":"2026012806301425700_R75","first-page":"5091","article-title":"Heat shock response and protein degradation: regulation of HSF2 by the ubiquitin-proteasome pathway.","volume-title":"Mol. Cell. Biol.","year":"1998"},{"key":"2026012806301425700_R76","first-page":"962","article-title":"p53\/p63\/p73 isoforms: an orchestra of isoforms to harmonise cell differentiation and response to stress.","volume-title":"Cell Death Differ.","year":"2006"},{"key":"2026012806301425700_R77","first-page":"9362","article-title":"Tumor-specific p73 up-regulation mediates p63 dependence in squamous cell carcinoma.","volume-title":"Cancer Res.","year":"2006"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/182\/10\/6600\/62682177\/8969.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/182\/10\/6600\/62682177\/8969.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T11:33:10Z","timestamp":1769599990000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/182\/10\/6600\/8006966"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,5]]},"references-count":77,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2009,5,15]]},"published-print":{"date-parts":[[2009,5,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.0801214","relation":{},"ISSN":["1550-6606","0022-1767"],"issn-type":[{"value":"1550-6606","type":"electronic"},{"value":"0022-1767","type":"print"}],"subject":[],"published-other":{"date-parts":[[2009,5]]},"published":{"date-parts":[[2009,5]]}}}