ArticleProceedings of the National Academy of Sciences of the United States of America2004
Chemical genetics to identify NFAT inhibitors: potential of targeting calcium mobilization in immunosuppression.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 47 citations in OpenAlex.
- Transcription factors in the development and treatment of immune disorders.Transcription · 2025Review
- NFAT as cancer target: mission possible?Biochimica et biophysica acta · 2014Review
- T cell IFN-γ suppression following alcohol and burn injury is independent of miRNA155.PloS one · 2014Article
- MicroRNA-124 suppresses the transactivation of nuclear factor of activated T cells by targeting multiple genes and inhibits the proliferation of pulmonary artery smooth muscle cells.The Journal of biological chemistry · 2013Article
- Cannabinoid receptor 2 suppresses leukocyte inflammatory migration by modulating the JNK/c-Jun/Alox5 pathway.The Journal of biological chemistry · 2013Article
- Noninvasive diagnosis of acute cellular rejection in liver transplant recipients: a proteomic signature validated by enzyme-linked immunosorbent assay.Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society · 2011Article
- Novel inhibitors of the calcineurin/NFATc hub - alternatives to CsA and FK506?Cell communication and signaling : CCS · 2009Article
- Systematizing serendipity for cardiovascular drug discovery.Circulation · 2009Review
- Multi-parameter phenotypic profiling: using cellular effects to characterize small-molecule compounds.Nature reviews. Drug discovery · 2009Review
- Molecular mechanisms of T-cell receptor and costimulatory molecule ligation/blockade in autoimmune disease therapy.Immunological reviews · 2009Review
- Inhibiting the calcineurin-NFAT (nuclear factor of activated T cells) signaling pathway with a regulator of calcineurin-derived peptide without affecting general calcineurin phosphatase activity.The Journal of biological chemistry · 2009Article
- TRPC6 mutations associated with focal segmental glomerulosclerosis cause constitutive activation of NFAT-dependent transcription.American journal of physiology. Cell physiology · 2009Article
- Therapeutic blockade of T-cell antigen receptor signal transduction and costimulation in autoimmune disease.Advances in experimental medicine and biology · 2008Review
- TRPC6 fulfills a calcineurin signaling circuit during pathologic cardiac remodeling.The Journal of clinical investigation · 2006Article
- Calcium-dependent activation of T-lymphocytes.Pflugers Archiv : European journal of physiology · 2005Review
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The development of more selective immunosuppressive agents to mitigate transplant rejection and autoimmune diseases requires effective strategies of blocking signaling pathways in T cells. Current immunosuppressive strategies use cyclosporin A (CsA) or FK506 to inhibit calcineurin, which dephosphorylates and promotes the nuclear import of nuclear factor of activated T cells (NFAT) transcription factors. These nuclear NFATs then transactivate cytokine genes that regulate proliferative responses of T cells. Both CsA and FK506 have debilitating side effects, including nephrotoxicity, hypertension, diabetes, and seizures, that argue for the development of alternative or complementary agents. To this end, we developed cell-based assays for monitoring NFAT dynamics in nonlymphoid cells to identify small molecules that inhibit NFAT nuclear import. Interestingly, we found that the majority of these small molecules suppress NFAT signaling by interfering with "capacitative" or "store-operated" calcium mobilization, thus raising the possibility that such mobilization processes are relevant targets in immunosuppression therapy. Further, these small molecules also show dose-dependent suppression of cytokine gene expression in T cells. Significantly, the IC(50) of CsA in primary T cells was reduced by the addition of suboptimal concentrations of these compounds, suggesting the possibility that such small molecules, in combination with CsA, offer safer means of immunosuppression.
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