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 most important group of antifungals is the azoles (e.g. miconazole), which act by inhibiting lanosterol demethylase in the sterol biosynthesis pathway. Azole activity can be modulated through structural changes in lanosterol demethylase, altered expression of its gene ERG11, alterations in other sterol biosynthesis enzymes or altered expression of multidrug transporters. We present evidence that azole activity versus Saccharomyces cerevisiae is also modulated by Ca2+-regulated signalling. (i) Azole activity was reduced by the addition of Ca2+. Conversely, azole activity was enhanced by the addition of Ca2+ chelator EGTA. (ii) Three structurally distinct inhibitors (fluphenazine, calmidazolium and a W-7 analogue) of the Ca2+-binding regulatory protein calmodulin enhanced azole activity. (iii) Two structurally distinct inhibitors (cyclosporin and FK506) of the Ca2+-calmodulin-regulated phosphatase calcineurin enhanced azole activity. (iv) Strains in which the Ca2+ binding sites of calmodulin were eliminated and strains in which the calcineurin subunit genes were disrupted demonstrated enhanced azole sensitivity; conversely, a mutant with constitutively activated calcineurin phosphatase demonstrated decreased azole sensitivity. (v) CRZ1/TCN1 encodes a transcription factor regulated by calcineurin phosphatase; its disruption enhanced azole sensitivity, whereas its overexpression decreased azole sensitivity. All the above treatments had comparable effects on the activity of terbinafine, an inhibitor of squalene epoxidase within the sterol biosynthesis pathway, but had little or no effect on the activity of drugs with unrelated targets. (vi) Treatment of S. cerevisiae with azole or terbinafine resulted in transcriptional upregulation of genes FKS2 and PMR1 known to be Ca2+ regulated. A model to explain the role of Ca2+-regulated signalling in azole/terbinafine tolerance is proposed.
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PMID:Antifungal activity in Saccharomyces cerevisiae is modulated by calcium signalling. 1236 48

Much progress has been made in the last decade in identifying genes responsible for antifungal resistance in Candida albicans. Attention has focused on five major C. albicans genes: ABC transporter genes CDR1 and CDR2, major facilitator efflux gene MDR1, and ergosterol biosynthesis genes ERG11 and ERG3. Resistance involves mutations in 14C-lanosterol demethylase, targeted by fluconazole (FLZ) and encoded by ERG11, and mutations that up-regulate efflux genes that probably efflux the antifungals. Mutations that affect ERG3 mutations have been understudied as mechanism resistance among clinical isolates. In vitro resistance in clinical isolates typically involves step-wise mutations affecting more than one of these genes, and often unidentified genes. Different approaches are needed to identify these other genes. Very little is understood about reversible adaptive resistance of C. albicans despite its potential clinical significance; most clinical failures to control infections other than oropharyngeal candidiasis (OPC) occur with in vitro susceptible strains. Tolerance of C. albicans to azoles has been attributed to the calcineurin stress-response pathway, offering new potential targets for next generation antifungals. Recent studies have identified genes that regulate CDR1 or ERG genes. The focus of this review is C. albicans, although information on Saccharomyces cerevisiae or Candida glabrata is provided in areas in where Candida research is underdeveloped. With the completion of the C. albicans genomic sequence, and new methods for high throughput gene overexpression and disruption, rapid progress towards understanding the regulation of resistance, novel resistance mechanisms, and adaptive resistance is expected in the near future.
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PMID:An update on antifungal targets and mechanisms of resistance in Candida albicans. 1611 Jul 76

Epigenetic disorders play a key role in tumorigenesis and development, among which histone methylation abnormalities are common. While patients living with chronic myeloid leukemia in the chronic phase (CML-CP) have a good response to TKI, blastic phase (CML-BP) patients demonstrate poor efficacy and high fatality rates. However, while the mechanism of blast crisis of chronic myeloid leukemia remains unclear, high expression and activation of BCR-ABL are usually related to CML blast crisis transition. We found that histone H3 lysine 4 (H3K4) demethylase RBP2 expression is negatively correlated with BCR-ABL expression, which suggests a regulatory link between these two genes. We also discovered that RBP2 mediates the dephosphorylation of BCR-ABL by directly downregulating PTEN expression, depending on histone demethylase activity, while PTEN targets protein phosphatase activity of BCR-ABL, a phosphatase which directly dephosphorylates BCR-ABL. In clinical specimens, the mRNA expression of RBP2 was found to be positively correlated with that of PTEN. These data suggest that the under-expression of RBP2 promotes blast crisis transition by activating an RBP2/PTEN/BCR-ABL cascade.
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PMID:Histone demethylase RBP2 mediates the blast crisis of chronic myeloid leukemia through an RBP2/PTEN/BCR-ABL cascade. 3137 92