Disease relevance of FLR1

• Finally, we show that FLR1 overexpression confers resistance to diamide, diethylmaleate, and menadione but hypersensitivity to H(2)O(2), demonstrating that the Flr1p transporter participates in Yap1p-mediated oxidative stress response in S. cerevisiae [1].
• Correlation of in vitro fluconazole resistance of Candida isolates in relation to therapy and symptoms of individuals seropositive for human immunodeficiency virus type 1 [2].
• Epidemiology of oral candidiasis in HIV-infected patients: colonization, infection, treatment, and emergence of fluconazole resistance [3].
• Detection and significance of fluconazole resistance in oropharyngeal candidiasis in human immunodeficiency virus-infected patients [4].
• Molecular characterization of fluconazole resistance in a case of Candida albicans ocular infection [5].

High impact information on FLR1

• Some genes, such as YOR1, SNQ2, and FLR1, are clearly directly controlled by both classes of transcription factor, suggesting an important role for the corresponding membrane proteins [6].
• Expression of FLR1 transporter requires phospholipase C and is repressed by Mediator [7].
• FLR1 encodes a plasma membrane transporter that mediates resistance to benomyl [7].
• Several other mutations in the Mediator complex also result in significant derepression of FLR1 and greatly increased resistance to benomyl [7].
• Multiple Yap1p-binding sites mediate induction of the yeast major facilitator FLR1 gene in response to drugs, oxidants, and alkylating agents [1].

Chemical compound and disease context of FLR1

• Three Candida albicans genes, designated FCR (for fluconazole resistance), have been isolated by their ability to complement the fluconazole (FCZ) hypersensitivity of a Saccharomyces cerevisiae mutant lacking the transcription factors Pdr1p and Pdr3p [8].

Biological context of FLR1

• AP1-mediated multidrug resistance in Saccharomyces cerevisiae requires FLR1 encoding a transporter of the major facilitator superfamily [9].
• Our results show that (i) each of the three YREs is functional and important for the optimal transactivation of FLR1 by Yap1p and that (ii) the three YREs are not functionally equivalent, mutation of YRE3 being the most deleterious, followed by YRE2 and YRE1 [1].
• The FLR1 promoter contains three potential Yap1p response elements (YREs) at positions -148 (YRE1), -167 (YRE2), and -364 (YRE3) [1].
• Our conclusions were based on the higher susceptibility to these compounds of flr1Delta compared with wild-type and on the increased resistance of both flr1Delta and wild-type strains upon increased expression of FLR1 gene from a centromeric plasmid clone [10].
• The present study also provides, for the first time, evidence that the adaptation of yeast cells to growth in the presence of benomyl involves the dramatic activation of FLR1 gene expression during benomyl-induced latency (up to 400-fold) [10].

Anatomical context of FLR1

• FLR1 gene encodes a plasma membrane transporter of the major facilitator superfamily (MFS) conferring resistance to multiple drugs, in particular to benomyl [11].
• OBJECTIVE: To examine the impact of continuous versus intermittent fluconazole therapy on fungal colonization and fluconazole resistance in the oropharynx of HIV-infected patients [12].

Associations of FLR1 with chemical compounds

• YAP1 confers resistance to the fatty acid synthase inhibitor cerulenin through the transporter Flr1p in Saccharomyces cerevisiae [13].
• We show that the transcription of FLR1 is induced upon cell treatment with the oxidizing agents diamide, diethylmaleate, hydrogen peroxide, and tert-butyl hydroperoxide, the antimitotic drug benomyl, and the alkylating agent methylmethane sulfonate and that this induction is mediated by Yap1p through the three YREs [1].
• FLR1 gene (ORF YBR008c) is required for benomyl and methotrexate resistance in Saccharomyces cerevisiae and its benomyl-induced expression is dependent on pdr3 transcriptional regulator [10].
• In contrast to the S. cerevisiae flr1 mutant, deletion of CgFLR1 in C. glabrata only resulted in increased sensitivity to benomyl, diamide, and menadione, but not 4-NQO, cycloheximide, or fluconazole [14].
• The mutation T315A in Candida albicans sterol 14alpha-demethylase causes reduced enzyme activity and fluconazole resistance through reduced affinity [15].

Regulatory relationships of FLR1

• Results obtained using a FLR1-lacZ fusion in a plasmid indicate that the activation of FLR1 expression in benomyl-stressed cells is under the control of the transcriptional regulator Pdr3p [10].

Other interactions of FLR1

• Taken collectively, our results demonstrate that FLR1 represents a new YAP1-controlled multidrug resistance molecular determinant in S. cerevisiae [9].
• Transcriptional activation of FLR1 gene during Saccharomyces cerevisiae adaptation to growth with benomyl: role of Yap1p and Pdr3p [11].
• We report here that mutations in CKA2, identified through an insertional mutagenesis screen, confer fluconazole resistance [16].
• A whole-cell-based assay using Saccharomyces cerevisiae strains that overexpress Candida albicans CDR1 and MDR1 efflux pumps has been employed to screen natural product extracts for reversal of fluconazole resistance [17].
• Overexpression of Erg11p by the regulatable GAL1 promoter confers fluconazole resistance in Saccharomyces cerevisiae [18].

Analytical, diagnostic and therapeutic context of FLR1

• Northern blot analysis indicated that Cgap1p regulates the benomyl-induced expression of CgFLR1, a homolog of S. cerevisiae FLR1, which encodes a transporter of the major facilitator superfamily [14].
• High-level fluconazole resistance (50% inhibitory concentration, > 256 micrograms/ml) developed in the isolates after serial passage in medium containing 8, 16, or 128 micrograms of fluconazole per ml, but not in isolates passed in 4 micrograms of fluconazole per ml [19].
• Candida albicans strain diversity and fluconazole resistance were prospectively analyzed in oral strains from 29 adult human immunodeficiency virus (HIV)-positive patients followed for > 1 year who had five or more culture-positive clinic visits [20].

References