Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Many genes in the Candida albicans ergosterol biosynthetic pathway are controlled by the transcriptional activator Upc2p, which is upregulated in the presence of azole drugs and has been suggested to regulate its own transcription by an autoregulatory mechanism. The UPC2 promoter was cloned upstream of a luciferase reporter gene (RLUC). UPC2-RLUC activity was induced in response to ergosterol biosynthesis inhibitors and in response to anaerobicity. Under both conditions, induction correlates with the magnitude of sterol depletion. Azole inducibility in the parental strain was approximately 100-fold, and in a UPC2 homozygous deletion strain was 17-fold, suggesting that, in addition to autoregulation, UPC2 transcription is controlled by a novel, Upc2p-independent mechanism(s). Curiously, basal UPC2-RLUC activity was fivefold higher in the deletion strain, which may be an indirect consequence of the lower sterol level in this strain, or a direct consequence of repression by an autoregulatory mechanism. These results suggest that transcriptional regulation of UPC2 expression is important in the response to antifungal drugs, and that this regulation occurs through Upc2p-dependent as well as novel Upc2p-independent mechanisms.
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PMID:Candida albicans UPC2 is transcriptionally induced in response to antifungal drugs and anaerobicity through Upc2p-dependent and -independent mechanisms. 1875 8

The human fungal pathogen Candida albicans develops drug resistance after long-term exposure to azole drugs in the treatment of chronic candidiasis. Gain-of-function (GOF) mutations in the transcription factor Tac1 and the consequent expression of its targets, drug efflux pumps Cdr1 and Cdr2, are a common mechanism by which C. albicans acquires fluconazole resistance. The mechanism by which GOF mutations hyperactivate Tac1 is currently unknown. Here, we define a transcriptional activation domain (TAD) at the C terminus of Tac1. GOF mutations within the Tac1 TAD, outside the context of full-length Tac1, generally do not enhance its absolute potential as a transcriptional activator. Negative regulation of the Tac1 TAD by the Tac1 middle region is necessary for the activating effect of GOF mutations or fluphenazine to be realized. We have found that full-length Tac1, when hyperactivated by xenobiotics or GOF mutations, facilitates the recruitment of the Mediator coactivator complex to the CDR1 promoter. Azole resistance and the activation of Tac1 target genes, such as CDR1, are dependent on the Tac1 TAD and subunits of the Mediator tail module. The dependence of different Tac1 target promoters on the Mediator tail module, however, varies widely. Lastly, we show that hyperactivation of Tac1 is correlated with its Mediator-dependent phosphorylation, a potentially useful biomarker for Tac1 hyperactivation. The role of Mediator in events downstream of Tac1 hyperactivation in fluconazole-resistant clinical isolates is complex and provides opportunities and challenges for therapeutic intervention.
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PMID:Mediator Tail Module Is Required for Tac1-Activated CDR1 Expression and Azole Resistance in Candida albicans. 2880 20