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C. Richard Boland - One of the best experts on this subject based on the ideXlab platform.
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Immune response To JC Virus T anTigen in paTienTs wiTh and wiThouT colorecTal neoplasia
Gut microbes, 2014Co-Authors: Lindsay D. Butcher, Ajay Goel, Melissa Garcia, Mildred Arnold, Hideki Ueno, C. Richard BolandAbstract:JC Virus (JCV) is a polyomaVirus ThaT infecTs approximaTely 75% of The populaTion and encodes a T anTigen (T-Ag) gene, which is oncogenic and inacTivaTes The p53 and pRb/p107/p130 proTein families. Previous work in our lab has idenTified The presence of T-Ag in colorecTal neoplasms. While JCV remains in a laTenT sTaTe for The majoriTy of Those infecTed, we hypoThesized ThaT a disTurbance in immunological conTrol may permiT JCV To reacTivaTe, which may be involved in The developmenT of colorecTal neoplasia. Our aim was To deTermine The cell mediaTed immune response To JCV T-Ag, and deTermine if iT is alTered in paTienTs wiTh colorecTal adenomaTous polyps (AP) or cancers (CRC). Peripheral blood mononuclear cells (PBMCs) isolaTed from The blood of paTienTs undergoing colonoscopy or colorecTal surgery were sTimulaTed by a pepTide library covering The enTire T-Ag proTein of JCV. CyTokine producTion and T cell proliferaTion were evaluaTed following T-Ag sTimulaTion using Luminex and flow cyTomeTry assays. JCV T...
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John Cunningham Virus T-anTigen expression in anal carcinoma
Cancer, 2010Co-Authors: Sonia Ramamoorthy, Bikash Devaraj, Katsumi Miyai, Linda Luo, Yu Tsueng Liu, C. Richard Boland, Ajay Goel, John M. CarethersAbstract:BACKGROUND: Anal carcinoma is ThoughT To be driven by human papillomaVirus (HPV) infecTion Through inTerrupTing funcTion of cell regulaTory proTeins such as p53 and pRb. John Cunningham Virus (JCV) expresses a T-anTigen ThaT causes malignanT TransformaTion Through developmenT of aneuploidy and inTeracTion wiTh some of The same regulaTory proTeins as HPV. JCV T-anTigen is presenT in brain, gasTric, and colon malignancies, buT has noT been evaluaTed in anal cancers. The auThors examined a cohorT of anal cancers for JCV T-anTigen and correlaTed This wiTh clinicopaThologic daTa. METHODS: Archived anal carcinomas were analyzed for JCV T-anTigen expression. DNA from Tumor and normal Tissue was sequenced for JCV wiTh viral copies deTermined by quanTiTaTive polymerase chain reacTion and SouThern bloTTing. HPV and microsaTelliTe insTabiliTy (MSI) sTaTus was correlaTed wiTh JCV T-anTigen expression. RESULTS: Of 21 cases of anal cancer (mean age 49 years, 38% female), 12 (57%) were in human immunodeficiency Virus (HIV)-posiTive individuals. All 21 cancers expressed JCV T-anTigen, including 9 HPV-negaTive specimens. More JCV copies were presenT in cancer versus surrounding normal Tissue (mean 32.54 copies/μg DNA vs 2.98 copies/μg DNA, P = .0267). There was no correlaTion beTween disease sTage and viral copies, nor beTween viral copies and HIV-posiTive or -negaTive sTaTus (28.7 vs 36.34 copies/μg DNA, respecTively, P = .7804). In subseT analysis, no associaTion was found beTween JCV T-anTigen expression and HPV or MSI sTaTus. CONCLUSIONS: Anal carcinomas uniformly express JCV T-anTigen and conTain more viral copies compared wiTh surrounding normal Tissue. JCV and iTs T-anTigen oncogenic proTein, presumably Through inTerrupTion of cell regulaTory proTeins, may play a role in anal cancer paThogenesis. Cancer 2011. © 2010 American Cancer SocieTy.
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JC Virus T-anTigen expression in sporadic adenomaTous polyps of The colon
Cancer, 2008Co-Authors: Woon-tae Jung, Ajay Goel, C. Richard BolandAbstract:JC Virus (JCV), a member of The polyomaviridae family, ubiquiTously infecTs humans, and as many as 70% To 80% of The adulT populaTion have JCV-specific anTibodies.1,2 Epidemiological sTudies have demonsTraTed ThaT JCV infecTion Takes place during early childhood and usually remains subclinical. AfTer primary infecTion, JCV infecTion can be found in The kidneys, B lymphocyTes, and guT mucosa. However, under condiTions of severe immunosuppression such as AIDS, cancer chemoTherapy, or organ TransplanTaTion The Virus may become reacTivaTed and induce The faTal demyelinaTing disease, progressive mulTifocal leukoencephalopaThy (PML).3 In addiTion To iTs essenTial role in PML, There is mounTing evidence ThaT JCV may be associaTed wiTh several human cancers even in The absence of immunosuppression or PML. JCV genomic sequences and onco-genic T-anTigen (T-Ag) expression have been reporTed in a varieTy of human malignancies, including brain Tumors,4,5 colon cancer,6–9 gasTric cancer,10 and esophageal cancer.11 JCV is a 5.13 kb closed, circular, supercoiled, double-sTranded DNA Virus. The viral genome consisTs of 3 funcTional regions: The ‘early’ and ‘laTe’ coding regions and a noncoding regulaTory region. The early region encodes The large T-Ag and small T-anTigens (T-Ag), whereas The laTe region encodes The viral capsid proTeins (VP1, VP2, and VP3) and an agnoproTein ThaT is involved in viral assembly. The early and laTe regions are separaTed by a bidirecTional, noncoding regulaTory region, also known as The TranscripTional conTrol region (TCR). The TCR conTains The origin of replicaTion (ori), and The promoTer and enhancer elemenTs ThaT conTrol viral replicaTion.12,13 AlThough The precise mechanisms responsible for JCV-induced cellular TransformaTion and Tumor developmenT are noT compleTely undersTood, iT is believed ThaT T-Ag plays a criTical role in malignanT TransformaTion by inTeracTing wiTh several cell regulaTory proTeins, including p5314 and pRb,15 and also by modulaTing several criTical growTh signaling paThways, such as The insulin-like growTh facTor-I recepTor (IGF-IR)16 and WnT signaling paThways.17 ColorecTal cancer (CRC) develops Through a sTepwise progression of mulTiple geneTic and epigeneTic alTeraTions, which manifesT The TransiTion from normal colonic mucosa To adenocarcinomas via adenomas (or adenomaTous polyps) of The colorecTum. In CRCs, 3 Types of genomic insTabiliTy, microsaTelliTe insTabiliTy (MSI), chromosomal insTabiliTy (CIN), and The CpG island meThylaTor phenoType (CIMP), are frequenTly observed and can accounT for almosT all CRCs. In sporadic CRCs, CIN and CIMP are represenTed in almosT equal frequencies, and The MSI cancers arise as a consequence of meThylaTion of hMLH1, a key DNA mismaTch repair (MMR) gene.18 MSI is characTerized by accumulaTion of somaTic alTeraTions in The lengTh of simple repeaT sequences called microsaTelliTes19–21 and is represenTaTive of Tumors from herediTary nonpolyposis colorecTal cancer (HNPCC). MSI may be presenT in greaTer Than 95% of CRCs and in 50% To 80% of colorecTal adenomas in HNPCC paTienTs.22–26 Conversely, MSI in sporadic colorecTal Tumors may be presenT in 10% To 15% of sporadic CRCs,19–21,27–30 and in less Than 10% of sporadic adenomas.28,30,31 The molecular mechanisms responsible for boTh CIN and CIMP are elusive and are a maTTer of inTense invesTigaTion. RecenTly, work from our laboraTory reporTed ThaT JCV T-Ag expression frequenTly associaTes wiTh boTh CIN and CIMP CRCs and suggesTed ThaT This viral oncogene may be involved in CRC Through mulTiple mechanisms of geneTic and epigeneTic insTabiliTy.32 These daTa are consisTenT wiTh several previous sTudies where JCV sequences were frequenTly demonsTraTed in as much as 80% To 90% of CRCs,6,8,32,33 whereas T-Ag proTein expression was found in a smaller subseT of These neoplasms.8,32 InTeresTingly, in These sTudies iT was clearly noTed ThaT T-Ag expression was presenT in a Tumor-specific manner, and was never presenT in The corresponding nonneoplasTic Tissues.8,32 JCV T-Ag DNA sequences have also been found in adenomaTous polyps of The colon, buT no sTudies have invesTigaTed JCV T-Ag proTein expression in These premalignanT polyps.9,34 These sTudies provide a sTrong raTionale for The poTenTial role of T-Ag in colon Tumorigenesis. However, To appreciaTe The role of JCV infecTion and CRC iT would be meaningful To deTermine The Timing of JCV acTivaTion in The normal-adenoma-carcinoma mulTisTep process. To The besT of our knowledge no previous sTudies have inTerrogaTed This imporTanT quesTion, providing sTrengTh To The role of JCV in various gasTroinTesTinal cancers. In addiTion, unlike CRC, The relaTionship beTween JCV T-Ag expression and genomic insTabiliTy in precursor adenomas is also currenTly uncerTain. Therefore, The objecTives of our sTudy were To TesT The hypoThesis ThaT JCV is presenT, ThaT T-Ag is expressed in sporadic adenomaTous polyps of The colon, and To evaluaTe associaTions beTween JCV T-Ag expression and specific forms of genomic insTabiliTy in These lesions.
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The role of JC Virus in colorecTal carcinogenesis.
Cancer Epidemiology and Prevention Biomarkers, 2006Co-Authors: C. Richard BolandAbstract:CS01-02 We have hypoThesized ThaT infecTion of The gasTroinTesTinal TracT wiTh The polyomaVirus JC Virus (JCV) may be involved in The causaTion of colorecTal cancer (CRC). IT has been esTablished ThaT one can immorTalize cells and induce aneuploidy by infecTing Them wiTh The polyomaVirus SV-40, which encodes The Transforming oncogene, T-anTigen. JCV is closely relaTed To SV-40, encodes a T-anTigen gene, and 80-90% of The populaTion has anTibody TiTers To The Virus. We have demonsTraTed ThaT 89% of CRCs harbor DNA sequences of The T-anTigen from JC Virus; This was deTermined by PCR, and confirmed wiTh SouThern bloTTing, cloning, and sequencing DNA from human Tumor specimens. The viral copy number is low, buT There are 10-100 fold more copies of The Virus in cancers Than in The adjacenT normal mucosa from paTienTs wiTh CRC. We were also able To deTecT JCV sequences in xenografTs generaTed from primary human colon cancers. We demonsTraTed ThaT normal healThy adulTs carry JCV in The esophagus, sTomach, colon, and recTum, and every paTienT who had a prior hisTory of cancer or a colorecTal adenoma had JCV DNA in mucosal biopsies from The upper or lower GI TracT. Because of The ubiquiTous carriage of This Virus by humans, we looked for a mechanism ThaT would accounT for a dormanT sTaTe of The Virus in mosT individuals, and iTs acTivaTion in cancer. Viral gene expression is regulaTed by The TranscripTion conTrol region (TCR) or promoTer region of JCV. We found rearranged forms of The TCR, which could noT be found in The normal colon, in all CRCs ThaT had JCV. We have subsequenTly developed several laboraTory models To TesT The hypoThesis ThaT primary colonic cells can be infecTed by JCV. TransfecTion of The diploid CRC cell line HCT116 wiTh a cloned JCV T-anTigen gene induces CIN. TransfecTion of The diploid CRC cell line RKO wiTh a full-lengTh JCV genome leads To sTabilizaTion of β-caTenin in The nucleus, an inTeracTion beTween T-anTigen and p53 proTein, and leads To aneuploidy wiThin a week. We have also shown ThaT T-anTigen expression in human CRCs is significanTly associaTed wiTh promoTer meThylaTion, and The CpG island meThylaTor phenoType (CIMP). CIMP is The mosT common cause of microsaTelliTe insTabiliTy (MSI) in CRCs. Thus, JCV can be linked To all of The known causes of geneTic or epigeneTic insTabiliTy found in CRCs. We have recenTly found JCV DNA in human gasTric and pancreaTic cancers as well. These daTa demonsTraTe ThaT JCV is ubiquiTously presenT in The human gasTroinTesTinal TracT, is presenT in a varieTy of human GI cancers, and can be mechanisTically linked To CIN, CIMP, and MSI in CRCs. This Virus is a candidaTe as The Trigger of neoplasia in The gasTroinTesTinal TracT. References: Laghi L, Randolph AE, Chauhan DP, Marra G, Major EO, Neel JV, Boland CR. JC Virus DNA is presenT in The human colon and in colorecTal cancers. Proc NaTl Acad Sci 96:7484-7489, 1999. Ricciardiello L, Laghi L, RamamirTham P, Chang CL, Chang DK, Randolph AE, Boland CR. JC Virus DNA sequences are frequenTly presenT in The human upper and lower gasTroinTesTinal TracT. GasTroenTerology 119:1228-1235, 2000. Ricciardiello L, Chang DK, Laghi L, Goel A, Chang CL, Boland CR. Mad-1 is The exclusive JC Virus sTrain presenT in The human colon, and iTs TranscripTional conTrol region has a deleTed 98-bp sequence in colon cancer Tissues. J. Virology 75:1996-01, 2001. Ricciardiello L, Baglioni M, Giovannini C, Pariali M, Cenacchi G, RipalTi A, Landini MP, Sawa H, Nagashima K, Frisque RJ, Goel A, Boland CR, Tognon M, Roda E, and Bazzoli F. InducTion of chromosomal insTabiliTy in colonic cells by The human polyomaVirus JC Through a hiT and run mechanism. Cancer Research 63:7256-62, 2003 Laghi L, Randolph AE, Malesci A, Boland CR. ConsTrainTs imposed by supercoiling upon in viTro amplificaTion of polyomaVirus DNA. J Gen Virol 85(PT 11):3383-8, 2004. Niv Y, Goel A, and Boland CR. JC Virus and colorecTal cancer - a possible Trigger in The chromosomal insTabiliTy paThway. Curr Opin GasTroenTerol 21:85-9, 2005. Goel A, Li M-S, Nagasaka T, Shin SK, FuersT F, Ricciardiello L, Wasserman L, and Boland CR. AssociaTion of JC Virus T-anTigen expression wiTh The meThylaTor phenoType in sporadic colorecTal cancers. GasTroenTerology 130:1950-61, 2006. Shin SK, Boland CR and Goel A. Oncogenic T-anTigen of JC Virus is presenT in human gasTric cancer. Cancer 107:481-488, 2006, 2006.
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AssociaTion of JC Virus T-AnTigen Expression WiTh The MeThylaTor PhenoType in Sporadic ColorecTal Cancers
Gastroenterology, 2006Co-Authors: Ajay Goel, Sung Kwan Shin, Luigi Ricciardiello, Takeshi Nagasaka, Florentine Fuerst, Linda Wasserman, C. Richard BolandAbstract:Background & Aims: JC Virus (JCV) is a polyomaVirus ThaT ubiquiTously infecTs humans and has been implicaTed in various human cancers. JCV encodes a "Transforming" gene, T-anTigen (T-Ag), which is believed To mediaTe The oncogenic poTenTial of The Virus. We have previously shown ThaT JCV DNA sequences are usually presenT in human colorecTal cancers (CRCs), and we have provided in viTro evidence ThaT JCV can induce chromosomal insTabiliTy (CIN) in CRC cells. This sTudy TesTs The hypoThesis ThaT JCV T-Ag expression correlaTes wiTh one or more forms of genomic or epigeneTic insTabiliTy in sporadic CRCs. MeThods: We characTerized 100 sporadic CRCs for microsaTelliTe insTabiliTy (MSI) and CIN. PCR amplificaTions were performed for T-Ag sequences, and immunohisTochemical (IHC) sTaining was performed To deTecT T-Ag expression. De novo meThylaTion of The promoTer regions of nine puTaTive Tumor suppressor genes ThoughT To play a role in colorecTal carcinogenesis was sTudied by meThylaTion-specific PCR. ResulTs: JCV T-Ag DNA sequences were found in 77% of The CRCs and 56% of These cancers (or 43% of The ToTal) expressed T-Ag by IHC. SignificanT associaTions were observed beTween T-Ag expression and CIN in CRCs ( P = .017) and beTween T-Ag expression and promoTer meThylaTion of mulTiple genes ( P = .01). Conclusions: The associaTion beTween T-Ag expression and promoTer meThylaTion in CRC suggesTs ThaT This viral oncogene may induce meThylaTor phenoType and ThaT JCV may be involved in CRC Through mulTiple mechanisms of geneTic and epigeneTic insTabiliTy.
Kamel Khalili - One of the best experts on this subject based on the ideXlab platform.
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JC Virus T-AnTigen RegulaTes Glucose MeTabolic PaThways in Brain Tumor Cells
PloS one, 2012Co-Authors: Evan Noch, Ilker Kudret Sariyer, Jennifer Gordon, Kamel KhaliliAbstract:RecenT sTudies have reporTed The deTecTion of The human neuroTropic Virus, JCV, in a significanT populaTion of brain Tumors, including medulloblasTomas. Accordingly, expression of The JCV early proTein, T-anTigen, which has Transforming acTiviTy in cell culTure and in Transgenic mice, resulTs in The developmenT of a broad range of Tumors of neural cresT and glial origin. EvidenTly, The associaTion of T-anTigen wiTh a range of Tumor-suppressor proTeins, including p53 and pRb, and signaling molecules, such as β-caTenin and IRS-1, plays a role in The oncogenic funcTion of JCV T-anTigen. We demonsTraTe ThaT T-anTigen expression is suppressed by glucose deprivaTion in medulloblasToma cells and in glioblasToma xenografTs ThaT boTh endogenously express T-anTigen. MechanisTic sTudies indicaTe ThaT glucose deprivaTion-mediaTed suppression of T-anTigen is parTly influenced by 5′-acTivaTed AMP kinase (AMPK), an imporTanT sensor of The AMP/ATP raTio in cells. In addiTion, glucose deprivaTion-induced cell cycle arresT in The G1 phase is blocked wiTh AMPK inhibiTion, which also prevenTs T-anTigen downregulaTion. FurThermore, T-anTigen prevenTs G1 arresT and susTains cells in The G2 phase during glucose deprivaTion. On a funcTional level, T-anTigen downregulaTion is parTially dependenT on reacTive oxygen species (ROS) producTion during glucose deprivaTion, and T-anTigen prevenTs ROS inducTion, loss of ATP producTion, and cyToToxiciTy induced by glucose deprivaTion. AddiTionally, we have found ThaT T-anTigen is downregulaTed by The glycolyTic inhibiTor, 2-deoxy-D-glucose (2-DG), and The penTose phosphaTe inhibiTors, 6-aminonicoTinamide and oxyThiamine, and ThaT T-anTigen modulaTes expression of The glycolyTic enzyme, hexokinase 2 (HK2), and The penTose phosphaTe enzyme, Transaldolase-1 (TALDO1), indicaTing a poTenTial link beTween T-anTigen and meTabolic regulaTion. These sTudies poinT To The possible involvemenT of JCV T-anTigen in medulloblasToma proliferaTion and The meTabolic phenoType and may enhance our undersTanding of The role of viral proTeins in glycolyTic Tumor meTabolism, Thus providing useful TargeTs for The TreaTmenT of Virus-induced Tumors.
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Expression of JC Virus T-anTigen in a paTienT wiTh MS and glioblasToma mulTiforme.
Neurology, 2002Co-Authors: L. Del Valle, Sahnila Enam, Sidney Croul, Jennifer Gordon, Serena Delbue, Pasquale Ferrante, Kamel KhaliliAbstract:ObjecTive: To invesTigaTe The presence of human polyomaVirus JC Virus genome and The expression of The viral oncoproTein T-anTigen in neoplasTic cells of a paTienT wiTh MS and a glioblasToma mulTiforme. Background: The posTmorTem examinaTion of an immunocompeTenT paTienT wiTh a neurologic disorder revealed The concurrence of MS plaques in The whiTe maTTer of The brain and a glioblasToma mulTiforme in The region of The Thalamus. MeThods and ResulTs: PCR analysis of DNA from demyelinaTed plaques and The Tumor area using primers derived from specific regions of The JC Virus genome revealed The presence of viral DNA corresponding To The viral early and laTe genes. FurTher examinaTion of The samples for The JC Virus regulaTory region idenTified The presence of sequences idenTical To JC Virus Mad-4 and JC Virus W1 viral isolaTes in The Tumor and The demyelinaTed regions. ResulTs from immunohisTochemisTry showed The deTecTion of The viral early proTein, T-anTigen, and The cellular Tumor suppressor proTein, p53, in The nuclei of neoplasTic cells. InTeresTingly, expression of T-anTigen, buT noT p53, was observed in neurofilamenT-posiTive cells wiTh neuronal morphology and in glial fibrillary acidic proTein–posiTive asTrocyTes in The corTex juxTaposed To The MS plaques. ExaminaTion of viral laTe gene expression by immunohisTochemisTry showed no evidence for viral capsid proTeins, Thus ruling ouT producTive replicaTion of JC Virus in The Tumor and MS demyelinaTed plaques. Conclusions: These observaTions provide molecular and clinical evidence of The associaTion of JC Virus in The brain of a paTienT wiTh concurrenT glioblasToma mulTiforme and MS.
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Insulin recepTor subsTraTe 1 TranslocaTion To The nucleus by The human JC Virus T-anTigen.
The Journal of biological chemistry, 2002Co-Authors: Adam Lassak, Luis Del Valle, Francesca Peruzzi, Jin Ying Wang, Sahnila Enam, Sidney Croul, Kamel Khalili, Krzysztof ReissAbstract:Insulin recepTor subsTraTe 1 (IRS-1) is The major signaling molecule for The insulin and insulin-like growTh facTor I recepTors, which Transduces boTh meTabolic and growTh-promoTing signals, and has Transforming properTies when overexpressed in The cells. Here we show ThaT IRS-1 is TranslocaTed To The nucleus in The presence of The early viral proTein-T-anTigen of The human polyomaVirus JC. Nuclear IRS-1 was deTecTed in T-anTigen-posiTive cell lines and in T-anTigen-posiTive biopsies from paTienTs diagnosed wiTh medulloblasToma. The IRS-1 domain responsible for a direcT JC Virus T-anTigen binding was localized wiThin The N-Terminal porTion of IRS-1 molecule, and The binding was independenT from IRS-1 Tyrosine phosphorylaTion and was sTrongly inhibiTed by IRS-1 serine phosphorylaTion. In addiTion, compeTiTion for The IRS-1-T-anTigen binding by a dominanT negaTive muTanT of IRS-1 inhibiTed growTh and survival of JC Virus T-anTigen-Transformed cells in anchorage-independenT culTure condiTions. Based on These findings, we propose a novel role for The IRS-1-T-anTigen complex in conTrolling cellular equilibrium during viral infecTion. IT may involve uncoupling of IRS-1 from iTs surface recepTor and TranslocaTion of iTs funcTion To The nucleus.
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Insulin-like growTh facTor I recepTor signaling sysTem in JC Virus T anTigen-induced primiTive neuroecTodermal Tumors--medulloblasTomas.
Journal of neurovirology, 2002Co-Authors: Luis Del Valle, Adam Lassak, Francesca Peruzzi, Jin Ying Wang, Sidney Croul, Kamel Khalili, Krzysztof ReissAbstract:MedulloblasTomas represenT abouT 25% of all pediaTric inTracranial neoplasms. These highly malignanT Tumors arise from The cerebellum, affecTing mainly children beTween ages 5 and 15. AlThough The eTiology of medulloblasTomas has noT yeT been elucidaTed, several reporTs suggesT ThaT boTh The cellular proTein insulin-like growTh facTor I (IGF-I) and The early proTein of The human polyomaVirus JC (JCV T anTigen) may conTribuTe To The developmenT of These Tumors. The resulTs of This sTudy show a poTenTial funcTional cooperaTion beTween These Two proTeins in The process of malignanT TransformaTion. BoTh medulloblasToma cell lines and medulloblasToma biopsies are characTerized by The abundanT presence of The IGF-I recepTor (IGF-IR) and iTs major signaling molecule, insulin recepTor subsTraTe 1 (IRS-1). ImporTanTly, IRS-1 is TranslocaTed To The nucleus in The presence of The JCV T anTigen. Nuclear IRS-1 was deTecTed in T anTigen-posiTive cell lines and in T anTigen-posiTive biopsies from paTienTs diagnosed wiTh medulloblasToma. The IRS-1 domain responsible for a direcT JCV T anTigen binding was localized wiThin The N-Terminal porTion of IRS-1 molecule and The compeTiTion for IRS-1 T anTigen binding by a dominanT-negaTive muTanT of IRS-1 inhibiTed growTh and survival of JCV T anTigen-Transformed cells in anchorage-independenT culTure condiTion.
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Insulin-like growTh facTor I recepTor signaling sysTem in JC Virus T anTigen-induced primiTive neuroecTodermal Tumors—medulloblasTomas
Journal of Neurovirology, 2002Co-Authors: Luis Del Valle, Adam Lassak, Francesca Peruzzi, Jin Ying Wang, Sidney Croul, Kamel Khalili, Krzysztof ReissAbstract:MedulloblasTomas represenT abouT 25% of all pediaTric inTracranial neoplasms. These highly malignanT Tumors arise from The cerebellum, affecTing mainly children beTween ages 5 and 15. AlThough The eTiology of medulloblasTomas has noT yeT been elucidaTed, several reporTs suggesT ThaT boTh The cellular proTein insulin-like growTh facTor I (IGF-I) and The early proTein of The human polyomaVirus JC (JCV T anTigen) may conTribuTe To The developmenT of These Tumors. The resulTs of This sTudy show a poTenTial funcTional cooperaTion beTween These Two proTeins in The process of malignanT TransformaTion. BoTh medulloblasToma cell lines and medulloblasToma biopsies are characTerized by The abundanT presence of The IGF-I recepTor (IGF-IR) and iTs major signaling molecule, insulin recepTor subsTraTe 1 (IRS-1). ImporTanTly, IRS-1 is TranslocaTed To The nucleus in The presence of The JCV T anTigen. Nuclear IRS-1 was deTecTed in T anTigen‐posiTive cell lines and in T anTigen‐posiTive biopsies from paTienTs diagnosed wiTh medulloblasToma. The IRS-1 domain responsible for a direcT JCV T anTigen binding was localized wiThin The N-Terminal porTion of IRS-1 molecule and The compeTiTion for IRS-1 T anTigen binding by a dominanT-negaTive muTanT of IRS-1 inhibiTed growTh and survival of JCV T anTigen‐Transformed cells in anchorage-independenT culTure condiTion. Journal of NeuroVirology (2002) 8(suppl. 2), 138‐147.
Ole Petter Rekvig - One of the best experts on this subject based on the ideXlab platform.
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In vivo expression of a single viral DNA-binding proTein generaTes sysTemic lupus eryThemaTosus-relaTed auToimmuniTy To double-sTranded DNA and hisTones
Proceedings of the National Academy of Sciences of the United States of America, 1995Co-Authors: Ugo Moens, Ole Morten Seternes, Allan William Hey, Yngve Silsand, Terje Traavik, Bjarne Johansen, Ole Petter RekvigAbstract:AlThough The origin of auToimmune anTibodies To double-sTranded DNA is noT known, The variable-region sTrucTures of such anTibodies indicaTe ThaT They are produced in response To anTigen-selecTive sTimulaTion. In accordance wiTh This, resulTs from experimenTs using arTificial complexes of DNA and DNA-binding polypepTides for immunizaTions have indicaTed ThaT DNA may induce These anTibodies. Hence, The immunogeniciTy of DNA in vivo may depend upon oTher sTrucTures or processes ThaT may render DNA immunogenic. We reporT ThaT in vivo expression of a single DNA-binding proTein, The polyoma Virus T anTigen, is sufficienT To iniTiaTe producTion of anTi-double-sTranded DNA and anTi-hisTone anTibodies buT noT a panel of oTher auToanTigens. Expression of a muTanT, non-DNA-binding T anTigen did resulT in sTrong producTion of anTibodies To The T anTigen, buT only borderline levels of anTibodies To DNA and no deTecTable anTibodies To hisTones. Nonexpressing plasmid DNA conTaining The compleTe cDNA sequence for T anTigen did noT evoke such immune responses, indicaTing ThaT DNA by iTself is noT immunogenic in vivo. The resulTs represenT a concepTual advance in undersTanding a poTenTial molecular basis for iniTiaTion of auToimmuniTy in sysTemic lupus eryThemaTosus.
Terje Traavik - One of the best experts on this subject based on the ideXlab platform.
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A possible conTribuTory role of BK Virus infecTion in neuroblasToma developmenT.
Cancer research, 1999Co-Authors: Trond Flægstad, Per Arne Andresen, John Inge Johnsen, Samuel Kofi Asomani, Gunn-eli Jørgensen, Somasuntharam Vignarajan, Anita Kjuul, Per Kogner, Terje TraavikAbstract:The Tumor suppressor proTein p53 is aberranTly localized To The cyToplasm of neuroblasToma cells, compromising The suppressor funcTion of This proTein. Such Tumors are experimenTally induced in Transgenic mice expressing The large Tumor (T) anTigen of polyomaViruses. The oncogenic mechanisms of T anTigen include complex formaTion wiTh, and inacTivaTion of, The Tumor suppressor proTein p53. Samples from 18 human neuroblasTomas and five normal human adrenal glands were examined. BK Virus DNA was deTecTed in all neuroblasTomas and none of five normal adrenal glands by PCR. Using DNA in siTu hybridizaTion, polyomaviral DNA was found in The Tumor cells of 17 of 18 neuroblasTomas, buT in none of five adrenal medullas. Expression of The large T anTigen was deTecTed in The Tumor cells of 16 of 18 neuroblasTomas, buT in none of The five adrenal medullas. By double immunosTaining BK Virus T anTigen and p53 was colocalized To The cyToplasm of The Tumor cells. ImmunoprecipiTaTion revealed binding beTween The Two proTeins. The presence and expression of BK Virus in neuroblasTomas, buT noT in normal adrenal medulla, and colocalizaTion and binding To p53, suggesT ThaT This Virus may play a conTribuTory role in The developmenT of This neoplasm.
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In vivo expression of a single viral DNA-binding proTein generaTes sysTemic lupus eryThemaTosus-relaTed auToimmuniTy To double-sTranded DNA and hisTones
Proceedings of the National Academy of Sciences of the United States of America, 1995Co-Authors: Ugo Moens, Ole Morten Seternes, Allan William Hey, Yngve Silsand, Terje Traavik, Bjarne Johansen, Ole Petter RekvigAbstract:AlThough The origin of auToimmune anTibodies To double-sTranded DNA is noT known, The variable-region sTrucTures of such anTibodies indicaTe ThaT They are produced in response To anTigen-selecTive sTimulaTion. In accordance wiTh This, resulTs from experimenTs using arTificial complexes of DNA and DNA-binding polypepTides for immunizaTions have indicaTed ThaT DNA may induce These anTibodies. Hence, The immunogeniciTy of DNA in vivo may depend upon oTher sTrucTures or processes ThaT may render DNA immunogenic. We reporT ThaT in vivo expression of a single DNA-binding proTein, The polyoma Virus T anTigen, is sufficienT To iniTiaTe producTion of anTi-double-sTranded DNA and anTi-hisTone anTibodies buT noT a panel of oTher auToanTigens. Expression of a muTanT, non-DNA-binding T anTigen did resulT in sTrong producTion of anTibodies To The T anTigen, buT only borderline levels of anTibodies To DNA and no deTecTable anTibodies To hisTones. Nonexpressing plasmid DNA conTaining The compleTe cDNA sequence for T anTigen did noT evoke such immune responses, indicaTing ThaT DNA by iTself is noT immunogenic in vivo. The resulTs represenT a concepTual advance in undersTanding a poTenTial molecular basis for iniTiaTion of auToimmuniTy in sysTemic lupus eryThemaTosus.
Antonio Giordano - One of the best experts on this subject based on the ideXlab platform.
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Expression of a human polyomaVirus oncoproTein and Tumour suppressor proTeins in medulloblasTomas.
Molecular pathology : MP, 2001Co-Authors: L. Del Valle, Kamel Khalili, Antonio Giordano, J Baehring, C Lorenzana, Sidney CroulAbstract:Aims —AlThough The aeTiology of medulloblasToma remains elusive, several lines of evidence suggesT an associaTion wiTh The human neuroTropic polyomaVirus JC and iTs oncoproTein T anTigen. The Tumour forming properTies of JC Virus T anTigen are The resulT, aT leasT in parT, of iTs abiliTy To bind and inacTivaTe Tumour suppressor/cell cycle regulaTory proTeins, such as p53 and The reTinoblasToma family of proTeins. MeThods —To examine poTenTial relaTions beTween These facTors, immunohisTochemisTry was used To deTermine associaTions beTween The T anTigen and The expression of p53 and The reTinoblasToma proTeins pRb, p107, and Rb2/p130 in eighT medulloblasTomas. ResulTs —Only The Three medulloblasTomas wiTh T anTigen expression also showed nuclear posiTiviTy wiTh anTibodies To p53. AlThough immunohisTochemisTry deTecTed nuclear labelling for pRb in five of The cases, The Three ThaT were posiTive for T anTigen showed The highesT pRb labelling. The reTinoblasToma relaTed proTeins p107 and Rb2/p130 were also immunoposiTive in mosT T anTigen posiTive medulloblasTomas. Double label immunohisTochemisTry also demonsTraTed p53 and pRb posiTiviTy in The same cells ThaT were T anTigen posiTive. Conclusions —These correlaTions suggesT ThaT associaTions beTween T anTigen and p53 and/or T anTigen and pRb occur in some of These Tumours. These daTa provide indirecT evidence ThaT JC Virus, acTing Through T anTigen, mighT be involved in The formaTion and progression of medulloblasToma.
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reTinoblasToma relaTed proTein prb2 p130 and suppression of Tumor growTh in vivo
Journal of the National Cancer Institute, 1998Co-Authors: Candace M Howard, Kamel Khalili, Jennifer Gordon, Pier Paolo Claudio, Gary L Gallia, Giovan Giacomo Giordano, Walter W Hauck, Antonio GiordanoAbstract:Background: The RB/p105 and p107 genes of The reTinoblasToma family are Tumor suppressor genes whose proTeins are inacTivaTed by inTeracTion wiTh T-anTigen proTeins encoded by polyomaViruses (e.g., simian Virus 40 and human JC Virus), which have been found To be highly Tumorigenic in animals. A varieTy of indirecT evidence suggesTs ThaT anoTher member of The reTinoblasToma gene family, RB2/p130, is also a Tumor suppressor gene. To invesTigaTe The puTaTive Tumor suppressor acTiviTy of RB2/p130 more direcTly, we uTilized a TeTracycline-regulaTed gene expression sysTem To conTrol expression of The encoded proTein pRb2/p130 in JC Virus-induced hamsTer brain Tumor cells and To sTudy The effecTs of pRb2/p130 on The growTh of such Tumor cells in nude mice. The abiliTy of pRb2/p130 To inTeracT wiTh JC Virus T anTigen was also sTudied. MeThods: NorThern bloT hybridizaTion analyses were performed on samples of ToTal cellular RNA To measure RB2/p130 and β-acTin messenger RNA levels. ImmunoprecipiTaTion and wesTern bloT analyses were used To deTermine T-anTigen and pRb2/p130 proTein levels and To assess The phosphorylaTion sTaTus of These proTeins. Tumor cells were injecTed subcuTaneously inTo nude mice, and Tumor growTh, wiTh or wiThouT induced expression of pRb2/ p130, was moniTored. ResulTs: InducTion of pRb2/p130 expression broughT abouT a 3.2-fold, or 69% (95% confidence inTerval = 64%-73%), reducTion in final Tumor mass in nude mice. We also demonsTraTed ThaT JC Virus T anTigen binds hypophosphorylaTed pRb2/p130 and ThaT sTimulaTion of pRb2/p130 expression overcomes cellular TransformaTion mediaTed by This anTigen. Conclusion: Our findings supporT The hypoThesis ThaT RB2/p130 is a Tumor suppressor gene.
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ReTinoblasToma-RelaTed ProTein pRb2/p130 and Suppression of Tumor GrowTh In Vivo
Journal of the National Cancer Institute, 1998Co-Authors: Candace M Howard, Kamel Khalili, Jennifer Gordon, Pier Paolo Claudio, Gary L Gallia, Giovan Giacomo Giordano, Walter W Hauck, Antonio GiordanoAbstract:Background: The RB/p105 and p107 genes of The reTinoblasToma family are Tumor suppressor genes whose proTeins are inacTivaTed by inTeracTion wiTh T-anTigen proTeins encoded by polyomaViruses (e.g., simian Virus 40 and human JC Virus), which have been found To be highly Tumorigenic in animals. A varieTy of indirecT evidence suggesTs ThaT anoTher member of The reTinoblasToma gene family, RB2/p130, is also a Tumor suppressor gene. To invesTigaTe The puTaTive Tumor suppressor acTiviTy of RB2/p130 more direcTly, we uTilized a TeTracycline-regulaTed gene expression sysTem To conTrol expression of The encoded proTein pRb2/p130 in JC Virus-induced hamsTer brain Tumor cells and To sTudy The effecTs of pRb2/p130 on The growTh of such Tumor cells in nude mice. The abiliTy of pRb2/p130 To inTeracT wiTh JC Virus T anTigen was also sTudied. MeThods: NorThern bloT hybridizaTion analyses were performed on samples of ToTal cellular RNA To measure RB2/p130 and β-acTin messenger RNA levels. ImmunoprecipiTaTion and wesTern bloT analyses were used To deTermine T-anTigen and pRb2/p130 proTein levels and To assess The phosphorylaTion sTaTus of These proTeins. Tumor cells were injecTed subcuTaneously inTo nude mice, and Tumor growTh, wiTh or wiThouT induced expression of pRb2/ p130, was moniTored. ResulTs: InducTion of pRb2/p130 expression broughT abouT a 3.2-fold, or 69% (95% confidence inTerval = 64%-73%), reducTion in final Tumor mass in nude mice. We also demonsTraTed ThaT JC Virus T anTigen binds hypophosphorylaTed pRb2/p130 and ThaT sTimulaTion of pRb2/p130 expression overcomes cellular TransformaTion mediaTed by This anTigen. Conclusion: Our findings supporT The hypoThesis ThaT RB2/p130 is a Tumor suppressor gene.
