0000000000165656

AUTHOR

Daniela Poppe

showing 2 related works from this author

Azathioprine suppresses ezrin-radixin-moesin-dependent T cell-APC conjugation through inhibition of Vav guanosine exchange activity on rac proteins

2006

Abstract We have shown recently that the azathioprine metabolite 6-Thio-GTP causes immunosuppression by blockade of GTPase activation in T lymphocytes. In the present study, we describe a new molecular mechanism by which 6-Thio-GTP blocks GTPase activation. Although 6-Thio-GTP could bind to various small GTPases, it specifically blocked activation of Rac1 and Rac2 but not of closely related Rho family members such as Cdc42 and RhoA in primary T cells upon stimulation with αCD28 or fibronectin. Binding of 6-Thio-GTP to Rac1 did not suppress Rac effector coupling directly but blocked Vav1 exchange activity upon 6-Thio-GTP hydrolysis, suggesting that 6-Thio-GTP loading leads to accumulation of…

AdultCD4-Positive T-LymphocytesVAV1RHOAT cellImmunologyBlotting WesternAntigen-Presenting CellsFluorescent Antibody TechniqueRAC1ApoptosisEnzyme-Linked Immunosorbent AssayGTPaseCell CommunicationBiologyArticleAzathioprinemedicineImmunology and AllergyHumansAntigen-presenting cellProto-Oncogene Proteins c-vavNeurofibromin 2Flow CytometryMolecular biologyCell biologyrac GTP-Binding ProteinsRac GTP-Binding ProteinsEnzyme Activationmedicine.anatomical_structurebiology.proteinSignal transductionImmunosuppressive Agents
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CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes

2003

Azathioprine and its metabolite 6-mercaptopurine (6-MP) are immunosuppressive drugs that are used in organ transplantation and autoimmune and chronic inflammatory diseases such as Crohn disease. However, their molecular mechanism of action is unknown. In the present study, we have identified a unique and unexpected role for azathioprine and its metabolites in the control of T cell apoptosis by modulation of Rac1 activation upon CD28 costimulation. We found that azathioprine and its metabolites induced apoptosis of T cells from patients with Crohn disease and control patients. Apoptosis induction required costimulation with CD28 and was mediated by specific block- ade of Rac1 activation thro…

AdultCD4-Positive T-LymphocytesSTAT3 Transcription Factorrac1 GTP-Binding Proteinmedicine.medical_specialtyApoptosisRAC1AzathioprineProtein Serine-Threonine KinasesBiologyLymphocyte ActivationOrgan transplantationTioguanineCD28 AntigensAzathioprinemedicineHumansPhosphorylationProtein kinase ACells CulturedAgedKinaseCD28General MedicineMiddle AgedI-kappa B KinaseDNA-Binding ProteinsApoptosisImmunologyTrans-ActivatorsCommentaryCancer researchImmunosuppressive Agentsmedicine.drugJournal of Clinical Investigation
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