Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The binding of soluble HLA class I (sHLA-I) molecules to CD8 on EBV-specific CTL induced up-regulation of Fas ligand (FasL) mRNA and consequent sFasL protein secretion. This, in turn, triggered CTL apoptosis by FasL/Fas interaction. Molecular analysis of the biochemical pathways responsible for FasL up-regulation showed that sHLA-I/CD8 interaction firstly induced the recruitment of src-like p56(lck) and syk-like Zap-70 protein tyrosine kinases (PTK). Interestingly, p59(fyn) was activated upon the engagement of CD3/TCR complex but not upon the interaction of sHLA-I with CD8. In addition, sHLA-I/CD8 interaction, which is different from signaling through the CD3/TCR complex, did not induce nuclear translocation of AP-1 protein complex. These findings suggest that CD8- and CD3/TCR-mediated activating stimuli can recruit different PTK and transcription factors. Indeed, the engagement of CD8 by sHLA-I led to the activation of Ca2+ calmodulin kinase II pathway, which eventually was responsible for the NF-AT nuclear translocation. In addition, we found that the ligation of sHLA-I to CD8 recruited protein kinase C, leading to NF-kappaB activation. Both NF-AT and NF-kappaB were responsible for the induction of FasL mRNA and consequent CTL apoptosis. Moreover, FasL up-regulation and CTL apoptotic death were down-regulated by pharmacological specific inhibitors of Ca2+/calmodulin/calcineurin and Ca2+-independent protein kinase C signaling pathways. These findings clarify the intracellular signaling pathways triggering FasL up-regulation and apoptosis in CTL upon sHLA-I/CD8 ligation and suggest that sHLA-I molecules can be proposed as therapeutic tools to modulate immune responses.
 ...
PMID:Apoptosis of antigen-specific T lymphocytes upon the engagement of CD8 by soluble HLA class I molecules is Fas ligand/Fas mediated: evidence for the involvement of p56lck, calcium calmodulin kinase II, and Calcium-independent protein kinase C signaling pathways and for NF-kappaB and NF-AT nuclear translocation. 1630 29

The transcription factor NFATc1 plays an essential role in transducing signals from RANKL in osteoclast differentiation. To date, however, the specific transcriptional targets of NFATc1 are unknown. Expression of the beta3 integrin is required for normal osteoclast function. We therefore examined the role of NFATc1 in human beta3 integrin expression in osteoclast differentiation. Analysis of the mouse and human beta3 gene promoters revealed considerable sequence homology across a 1.3 kb region upstream of the transcription start site (TSS), with conserved NFAT binding elements present. The region -1242 to +29 (relative to the TSS) was cloned as a luciferase reporter construct (pB3-1.3) and a deletion construct removing to -997 (pB3-1) made. The deletion of 245 bp 5' removed three conserved NFAT sites including a consensus NFAT:AP-1 site. The pB3-1.3 reporter construct was induced by treatment with RANKL in the range 2.5-40 ng/ml and dose-dependently induced by co-transfection with human NFATc1 in RAW264.7 cells. The pB3-1 deletion construct was minimally induced with RANKL treatment and unresponsive to co-transfected NFATc1. Direct NFAT binding to two of the consensus NFAT sites within this 245 bp 5' region was demonstrated by EMSA and supershift with anti-NFAT antibodies. Mutation of two of the conserved NFAT sites in the -1242 to -997 fragment was required to prevent binding. The double NFAT mutant, in the context of the full-length promoter was unresponsive to RANKL treatment or co-transfected NFATc1. We generated cell-permeable TAT-dominant-negative (dn)NFATc1 fusion proteins to assess the effect of blockade of NFAT signaling. Transduction with dnNFAT inhibited RANKL induction of the human beta3 integrin promoter. Involvement of the NFATc1-calcineurin pathway in regulating the human beta3 integrin promoter was further confirmed using the calcineurin pathway inhibitory peptide 11R-VIVIT. Together these results establish the beta3 gene as a direct target of NFATc1 in RANKL-dependent osteoclast formation.
 ...
PMID:NFATc1 regulation of the human beta3 integrin promoter in osteoclast differentiation. 1651 93

Cathepsin K is essential for normal bone resorption. Osteoclasts synthesize and secrete cathepsin Kinto the extracellular compartment at the attachment site between osteoclasts and the bone surface, wherein the organic matrix is subsequently degraded by cathepsin K. RANKL, NFAT, Mitf, and various components of AP-1 enhance osteoclast formation and bone resorption, whereas IFN-gamma, calcitonin, estradiol, and calcium inhibit it. These agents appear to act correspondingly to alter cathepsin K mRNA and protein expression in order to stimulate and suppress the osteoclast's resorbing potential. RANKL signaling via the calcineurin-calcium-NFAT signaling cascade plays a significant role in the regulation of cathepsin K expression. Activation via p38 and the micropthalmia transcription factor also enhances cathepsin K expression. Future studies will be needed to elucidate the relative roles of various signaling pathways at different stages of osteoclast formation and activation and to determine whether genetically disrupting these pathways can modulate bone resorption with or without impeding other osteoclast functions.
 ...
PMID:The regulation of cathepsin K gene expression. 1683 15

T lymphocytes cultured under the low-shear stress environment of modeled microgravity demonstrate an inhibition of activation in response to T-cell receptor (TCR)-mediated signaling. Modeled microgravity culture-induced inhibition mimics the inhibition observed during spaceflight. This work investigates the molecular signaling events of interleukin 2 transcription activation in modeled microgravity as generated with clinorotation. Under normal conditions, NFAT (nuclear factor of activated T cells) is dephosphorylated and activated with sustained calcium (Ca++) influx and calcineurin activity, whereas AP-1 is activated by protein kinase C (PKC) and Ras-mediated pathways. Purified human T lymphocytes are shown to exhibit differential inhibition of transcription factor activation in modeled microgravity. Activation of AP-1 is blocked with clinorotation, whereas NFAT dephosphorylation occurs. This work supports the theory that modeled microgravity differentially blocks the activation of distinct signaling mechanism.
 ...
PMID:Clinorotation differentially inhibits T-lymphocyte transcription factor activation. 1684 35

Leptomycin B (LMB) is a Streptomyces metabolite that causes the specific inhibition of the nuclear export of proteins containing a nuclear export signal (NES). LMB was reported to inhibit cell cycle progression in fission yeast and mammalian cells, however, the mechanism underlying LMB-induced cell cycle arrest is still obscure. In this study, we found that in serum-starved NIH3T3 cells, LMB inhibited serum-induced cyclin D1 expression at the level of transcription. However, this inhibition was reversed by inhibitors of protein phosphatase 2A (PP2A). Furthermore, we found that PP2A accumulated in the nucleus upon treatment with LMB. The finding prompted us to identify the functional NES in PP2A catalytic subunit alpha. These results indicated that LMB inhibited the chromosomal region maintenance 1 (CRM1)-dependent nuclear export of PP2A, resulting in sustained dephosphorylation in the nucleus. Although phosphorylation of c-Jun at Ser-63 is required for activator protein 1 (AP-1)-dependent expression of cyclin D1, it decreased in LMB-treated cells compared to untreated cells. Moreover, the inhibitors of PP2A restored the levels of c-Jun phosphorylated at Ser-63. We propose that inhibition of cyclin D1 expression by LMB is mediated by the LMB-induced nuclear accumulation of PP2A, leading to sustained dephosphorylation of c-Jun at Ser-63, which leads to inactivation of the transcription of the AP-1-responsive cyclin D1 gene.
 ...
PMID:Involvement of protein phosphatase 2A nuclear accumulation and subsequent inactivation of activator protein-1 in leptomycin B-inhibited cyclin D1 expression. 1696 87

T cell Ig and mucin domain protein 2 (TIM-2) has been shown to regulate T cell activation in vitro and T cell-mediated disease in vivo. However, it is still not clear whether TIM-2 acts mainly to augment T cell function or to inhibit it. We have directly examined the function of TIM-2 in murine and human T cell lines. Our results indicate that expression of TIM-2 significantly impairs the induction of NFAT and AP-1 transcriptional reporters by not only TCR ligation but also by the pharmacological stimuli PMA and ionomycin. This does not appear to be due to a general effect on cell viability, and the block in NFAT activation can be bypassed by expression of activated alleles of Ras or calcineurin, or MEK kinase, in the case of AP-1. Thus, our data are consistent with a model whereby TIM-2 inhibits T cell activation.
 ...
PMID:Cutting edge: inhibition of T cell activation by TIM-2. 1701 78

Mycobacterium leprae, the causative agent of leprosy, challenges host defense mechanism by impairing the signal transduction of T cells which leads to downregulation of T cell proliferation, mainly as a consequence of interference with IL-2 production. In this study we sought to identify how soluble forms of M. leprae antigen(s) or particulate (liposome) delivery of the same antigens with two immunomodulators Murabutide and T cell peptide of Trat protein influence the transcription of IL-2 gene in anergic T cells of lepromatous patients. It was demonstrated that MLCwA/ManLAM stimulated cells of BL/LL patients showed defects in both jun-NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) activities there by resulting in decreased AP-1 activity. Additionally these cells showed reduced calcium levels, PKC activity and calcineurin (CN) activity. This led to impaired nuclear translocation of NFkappaB and NFAT in these patients. In contrast, when same M. leprae antigen(s) were incorporated with the two immunomodulators in liposomal form, increased transcription of IL-2 gene was observed especially in BL/LL patients which appears to be due to, at least in part, to increased expression of AP-1 Fos and Jun family members, NFkappaB and NFAT1 proteins. The increased expression of these transcription factors correlated with increased ERK/JNK, PKC and CN activities in these patients. Since activation of ERK/JNK/PKC kinases and CN phosphatase are required for stimulation of IL-2 transcription, these data provide a molecular explanation for the block in IL-2 production by M. leprae antigens. Thus the above study revealed suppression of all the three distinct biochemical pathways, viz. Ca-CN-NFAT pathway, PKC-NF-kappaB pathway, and MAPK-AP-1 pathway by M. leprae antigen(s) in anergized T cells of lepromatous patients which were activated by liposomal delivery of M. leprae antigens containing the two immunomodulators leading to optimal induction of IL-2 gene expression, which was required for the activation, and proliferation of T cells in lepromatous patients.
 ...
PMID:Alterations in T cell signal transduction by M. leprae antigens is associated with downregulation of second messengers PKC, calcium, calcineurin, MAPK and various transcription factors in leprosy patients. 1704 60

T cells from patients with systemic lupus erythematosus (SLE) are characterized by heightened TCR-initiated free intracytoplasmic calcium responses. We demonstrate that activated T cells from SLE patients, but not from rheumatoid arthritis patients, displayed higher levels of the calcineurin-dependent transcription factor NF-ATc2 in the nucleus compared with control T cells. DNA NF-AT-binding activity was also increased, as was the amount of NF-ATc2 bound to the promoters of CD154 (CD40L) and IL-2 genes. Nevertheless, although high NF-ATc2 levels translated into higher CD154 transcription in SLE, IL-2 transcription was decreased. The absence of important transcriptional activators (AP-1, NF-kappaBeta) and the presence of transcriptional repressors (cAMP response element modulator) on the IL-2 promoter explain this dichotomous effect.
 ...
PMID:Increased levels of NF-ATc2 differentially regulate CD154 and IL-2 genes in T cells from patients with systemic lupus erythematosus. 1723 47

Valproic acid (VPA) is widely used to treat epilepsy and manic-depressive illness. Although VPA has been reported to exert a variety of biochemical effects, the exact mechanisms underlying its therapeutic effects remain elusive. To gain further insights into the molecular mechanisms of VPA action, a genetic screen for fission yeast mutants that show hypersensitivity to VPA was performed. One of the genes that we identified was vps45+, which encodes a member of the Sec1/Munc18 family that is implicated in membrane trafficking. Notably, several mutations affecting membrane trafficking also resulted in hypersensitivity to VPA. These include ypt3+ and ryh1+, both encoding a Rab family protein, and apm1+, encoding the mu1 subunit of the adaptor protein complex AP-1. More importantly, VPA caused vacuolar fragmentation and inhibited the glycosylation and the secretion of acid phosphatase in wild-type cells, suggesting that VPA affects membrane trafficking. Interestingly, the cell-wall-damaging agents such as micafungin or the inhibition of calcineurin dramatically enhanced the sensitivity of wild-type cells to VPA. Consistently, VPA treatment of wild-type cells enhanced their sensitivity to the cell-wall-digesting enzymes. Altogether, our results suggest that VPA affects membrane trafficking, which leads to the enhanced sensitivity to cell-wall damage in fission yeast.
 ...
PMID:Valproic acid affects membrane trafficking and cell-wall integrity in fission yeast. 1728 31

Cyclosporine-A (CyA) and FK506 are potent immunosuppressive agents because of their ability to suppress the production of Th1 cytokines including interleukin (IL)-12. However, the mechanisms underlying the inhibitory effects of CyA and FK506 on the production of IL-12p40, a critical component of IL-12, remain unknown. Both CyA and FK506 are potent inhibitors of calcineurin in the calcium signaling pathway. Interestingly, calcium and phosphoinositide 3-kinase (PI3K) signaling pathways have been shown to negatively regulate lipopolysaccharide (LPS)-induced murine IL-12p40 production. Contrary to these observations, we show that LPS-induced IL-12p40 production in human monocytic cells is positively regulated by the calcium pathway and in particular by calmodulin-(CaM) and CaM-dependent protein kinase-II (CaMK-II)-activated PI3K. Furthermore, LPS-induced IL-12p40 production was regulated by the p110alpha catalytic subunit of PI3K. Moreover, LPS induced IL-12p40 production through the CaM/CaMK-II-activated NFkappaB and AP-1 transcription factors. LPS-induced IL-12p40 production is known to be regulated by the c-Jun N-terminal kinase (JNK) pathway. Importantly, both CyA and FK506 down-regulated LPS-induced IL-12p40 transcription by inhibiting CaM/CaMK-II-activated PI3K and their downstream transcription factors NFkappaB and AP-1 independent of the JNK pathway.
 ...
PMID:Cyclosporin A and FK506 inhibit IL-12p40 production through the calmodulin/calmodulin-dependent protein kinase-activated phosphoinositide 3-kinase in lipopolysaccharide-stimulated human monocytic cells. 2231 83


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>