Affinity-Driven Peptide Selection of an NFAT Inhibitor More Selective Than Cyclosporin A

Aramburu, J.; Yaffe, Michael B.; López-Rodrı́guez, Cristina; Cantley, Lewis C.; Hogan, Patrick G.; Rao, Anjana

doi:10.1126/science.285.5436.2129

Cited by 561 publications

(643 citation statements)

References 33 publications

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“…4B). In contrast, MIP1␣ mRNA expression was inhibited around 40 -50% by CsA at 6 and 12 h. The data are consistent with previous studies that showed the presence of functional NF-AT sites in the MIP1␣ promoter-enhancer region (47). Accordingly, these data suggest that AngII did enhance mRNA expression of both Th1-associated chemokines (IP-10 and MIP1␣), mainly via AT1 on MC, though their transcriptional regulation may be different.…”

Section: Angii-induced Chemotactic Activity Involves Can/nf-at and Nfsupporting

confidence: 91%

Susceptibility to T Cell-Mediated Injury in Immune Complex Disease Is Linked to Local Activation of Renin-Angiotensin System: The Role of NF-AT Pathway

Suzuki

Gómez-Guerrero

Shirato³

et al. 2002

The Journal of Immunology

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FcR provides a critical link between ligands and effector cells in immune complex diseases. Emerging evidence reveals that angiotensin (Ang)II exerts a wide variety of cellular effects and contributes to the pathogenesis of inflammatory diseases. In anti-glomerular basement membrane Ab-induced glomerulonephritis (GN), we have previously noted that FcR-deficient mice (γ−/−) surviving from lethal initial damage still developed mesangial proliferative GN, which was drastically prevented by an AngII type 1 receptor (AT1) blocker. We further examined the mechanisms by which renin-Ang system (RAS) participates in this immune disease. Using bone marrow chimeras between γ−/− and AT1−/− mice, we found that glomerular injury in γ−/− mice was associated with CD4+ T cell infiltration depending on renal AT1-stimulation. Based on findings in cutaneous delayed-type hypersensitivity, we showed that AngII-activated renal resident cells are responsible for the recruitment of effector T cells. We next examined the chemotactic activity of AngII-stimulated mesangial cells, as potential mechanisms coupling RAS and cellular immunity. Chemotactic activity for T cells and Th1-associated chemokine (IFN-γ-inducible protein-10 and macrophage-inflammatory protein 1α) expression was markedly reduced in mesangial cells from AT1−/− mice. Moreover, this activity was mainly through calcineurin-dependent NF-AT. Although IFN-γ-inducible protein-10 was NF-κB-dependent, macrophage-inflammatory protein 1α was dominantly regulated by NF-AT. Furthermore, AT1-dependent NF-AT activation was observed in injured glomeruli by Southwestern histochemistry. In conclusion, our data indicate that local RAS activation, partly via the local NF-AT pathway, enhances the susceptibility to T cell-mediated injury in anti-glomerular basement membrane Ab-induced GN. This novel mechanism affords a rationale for the use of drugs interfering with RAS in immune renal diseases.

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Section: Angii-induced Chemotactic Activity Involves Can/nf-at and Nfsupporting

confidence: 91%

Susceptibility to T Cell-Mediated Injury in Immune Complex Disease Is Linked to Local Activation of Renin-Angiotensin System: The Role of NF-AT Pathway

Suzuki

Gómez-Guerrero

Shirato³

et al. 2002

The Journal of Immunology

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“…As shown in Figure 3A, we found that treatment of cells with either FK506 or cyclosporin A, two structurally unrelated, highly specific calcineurin inhibitors, both effectively attenuated the inhibitory effects of PGF2a on adipocyte differentiation, as determined by Oil Red O staining. Similarly, we found that the retroviral-mediated expression of VIVIT-GFP, a previously characterized specific calcineurin inhibitory peptide [Aramburu et al, 1999], also significantly rescued the inhibitory effects of PGF2a on adipocyte differentiation. The role of calcineurin in mediating the inhibitory effects of PGF2a on adipocyte differentiation was further confirmed by analyzing the expression of the late, mature adipocyte-specific marker gene, aP2.…”

Section: The Calcineurin Phosphatase Plays a Critical Role In Mediatisupporting

confidence: 66%

Prostaglandin F2α inhibits adipocyte differentiation via a Gαq‐Calcium‐Calcineurin‐Dependent signaling pathway

Liu

Clipstone

2006

J of Cellular Biochemistry

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Prostaglandin F2a (PGF2a) is a potent physiological inhibitor of adipocyte differentiation, however the specific signaling pathways and molecular mechanisms involved in mediating its anti-adipogenic effects are not well understood. In the current study, we now provide evidence that PGF2a inhibits adipocyte differentiation via a signaling pathway that requires heterotrimeric G-protein Gaq subunits, the elevation of the intracellular calcium concentration ([Ca 2þ ] i ), and the activation of the Ca 2þ /calmodulin-regulated serine/threonine phosphatase calcineurin. We show that while this pathway acts to inhibit an early step in the adipogenic cascade, it does not interfere with the initial mitotic clonal expansion phase of adipogenesis, nor does it affect either the expression, DNA binding activity or differentiation-induced phosphorylation of the early transcription factor C/EBPb. Instead, we find that PGF2a inhibits adipocyte differentiation via a calcineurin-dependent mechanism that acts to prevent the expression of the critical pro-adipogenic transcription factors PPARg and C/EBPa. Furthermore, we demonstrate that the inhibitory effects of PGF2a on both the expression of PPARg and C/EBPa and subsequent adipogenesis can be attenuated by treatment of preadipocytes with the histone deacetylase (HDAC) inhibitor trichostatin A. Taken together, these results indicate that PGF2a inhibits adipocyte differentiation via a Gaq-Ca 2þ -calcineurin-dependent signaling pathway that acts to block expression of PPARg and C/EBPa by a mechanism that appears to involves an HDAC-sensitive step.

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“…NCI3 might have fewer side effects than the commonly used immunosuppressive drugs CsA and FK506, because a compound blocking the calcineurin-NFAT signaling and not the general phosphatase activity of calcineurin is expected to have a lower toxicity [14,20]. However, it is unclear to what extent the toxicity of CsA and FK506 is due to inhibition of NFAT, to interference with dephosphorylation of other calcineurin substrates, to inhibition of the peptidyl-prolyl-cis/ trans-isomerase activity of the immunophilins, or to other non-calcineurin-dependent effects.…”

Section: Discussionmentioning

confidence: 99%

“…The NFAT analogue VIVIT peptide was shown to bind efficiently to calcineurin [20]. We evaluated whether NCI3 inhibits this interaction by using FITC-labeled calcineurin, biotinylated 17mer VIVIT peptide and streptavidin-coupled microspheres.…”

Section: Nci3 Partially Interferes With the Calcineurin Vivit Peptidementioning

confidence: 99%

Inhibition of calcineurin‐NFAT signaling by the pyrazolopyrimidine compound NCI3

et al. 2007

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Dephosphorylation of NFAT by the Ca 2+ -calmodulin-dependent Ser/Thr protein phosphatase calcineurin is a bottleneck of T cell receptor-dependent activation of T cells. In dimeric complexes with immunophilins, the immunosuppressants cyclosporine A (CsA) and tacrolimus (FK506) block this process by inhibition of the enzymatic activity of calcineurin. We have identified the pyrazolopyrimidine compound NCI3 as a novel inhibitor of calcineurin-NFAT signaling. Similar to CsA and FK506, NCI3 inhibits dephosphorylation and nuclear translocation of NFAT, IL-2 production and proliferation of stimulated human primary T cells with IC 50 values from 2 to 4.5 lM. However, contrary to CsA and FK506, NCI3 neither blocks calcineurin`s phosphatase activity nor requires immunophilins for inhibiting NFAT activation. Our data suggest that NCI3 binds to calcineurin and causes an allosteric change interfering with NFAT dephosphorylation in vivo but not in vitro. NCI3 acts not only on the endogenous calcineurin but also on a C-terminally truncated, constitutively active version of calcineurin. The novel inhibitor described herein will be useful in better defining the cellular regulation of calcineurin activation and may serve as a lead for the development of a new type of immunosuppressants acting not by direct inhibition of the calcineurin phosphatase activity.

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Affinity-Driven Peptide Selection of an NFAT Inhibitor More Selective Than Cyclosporin A

Cited by 561 publications

References 33 publications

Susceptibility to T Cell-Mediated Injury in Immune Complex Disease Is Linked to Local Activation of Renin-Angiotensin System: The Role of NF-AT Pathway

Susceptibility to T Cell-Mediated Injury in Immune Complex Disease Is Linked to Local Activation of Renin-Angiotensin System: The Role of NF-AT Pathway

Prostaglandin F2α inhibits adipocyte differentiation via a Gαq‐Calcium‐Calcineurin‐Dependent signaling pathway

Inhibition of calcineurin‐NFAT signaling by the pyrazolopyrimidine compound NCI3

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