The bZip transcription factor Cgap1p is involved in multidrug resistance and required for activation of multidrug transporter gene CgFLR1 in Candida glabrata

ABSTRACTInfections with the opportunistic yeastCandida glabratahave increased dramatically in recent years. Antifungal therapy of yeast infections commonly employs azoles, such as fluconazole (FLC), butC. glabratafrequently develops resistance to these inhibitors of ergosterol biosynthesis. The pyrimidine analog flucytosine (5-fluorocytosine [5FC]) is highly active versusC. glabratabut is now rarely used clinically due to similar concerns over resistance and, a related concern, the toxicity associated with high doses used to counter resistance. Azole-5FC combination therapy would potentially address these concerns; however, previous studies suggest that 5FC may antagonize azole activity versusC. glabrata. Here, we report that 5FC at subinhibitory concentrations antagonized the activity of FLC 4- to 16-fold versus 8 of 8C. glabrataisolates tested. 5FC antagonized the activity of other azoles similarly but had only indifferent effects in combination with unrelated antifungals. Since azole resistance inC. glabrataresults from transcription factor Pdr1-dependent upregulation of the multidrug transporter geneCDR1, we reasoned that 5FC antagonism might be similarly mediated. Indeed, 5FC-FLC antagonism was abrogated inpdr1Δ andcdr1Δ strains. In further support of this hypothesis, 5FC exposure inducedCDR1expression 6-fold, and this upregulation was Pdr1 dependent. In contrast to azoles, 5FC is not a Cdr1 substrate and so its activation of Pdr1 was unexpected. We observed, however, that 5FC exposure readily induced petite mutants, which exhibit Pdr1-dependentCDR1upregulation. Thus, mitochondrial dysfunction resulting in Pdr1 activation is the likely basis for 5FC antagonism of azole activity versusC. glabrata.

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Candida glabrata Drug:H+Antiporter CgQdr2 Confers Imidazole Drug Resistance, Being Activated by Transcription Factor CgPdr1

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00811-12 ◽

2013 ◽

Vol 57 (7) ◽

pp. 3159-3167 ◽

Cited By ~ 42

Author(s):

Catarina Costa ◽

Carla Pires ◽

Tânia R. Cabrito ◽

Adeline Renaudin ◽

Michiyo Ohno ◽

...

Keyword(s):

Drug Resistance ◽

Transcription Factor ◽

Multidrug Resistance ◽

Candida Glabrata ◽

Antifungal Drugs ◽

Antifungal Drug ◽

Major Facilitator Superfamily ◽

Pathogenic Yeast ◽

Content Type ◽

Antifungal Drug Resistance

ABSTRACTThe widespread emergence of antifungal drug resistance poses a severe clinical problem. Though predicted to play a role in this phenomenon, the drug:H+antiporters (DHA) of the major facilitator superfamily have largely escaped characterization in pathogenic yeasts. This work describes the first DHA from the pathogenic yeastCandida glabratareported to be involved in antifungal drug resistance, theC. glabrata QDR2(CgQDR2) gene (ORFCAGL0G08624g). The expression ofCgQDR2inC. glabratawas found to confer resistance to the antifungal drugs miconazole, tioconazole, clotrimazole, and ketoconazole. By use of a green fluorescent protein (GFP) fusion, the CgQdr2 protein was found to be targeted to the plasma membrane inC. glabrata. In agreement with these observations,CgQDR2expression was found to decrease the intracellular accumulation of radiolabeled clotrimazole inC. glabrataand to play a role in the extrusion of this antifungal from preloaded cells. Interestingly, the functional heterologous expression ofCgQDR2in the model yeastSaccharomyces cerevisiaefurther confirmed the role of this gene as a multidrug resistance determinant: its expression was able to complement the susceptibility phenotype exhibited by itsS. cerevisiaehomologue,QDR2, in the presence of imidazoles and of the antimalarial and antiarrhythmic drug quinidine. In contrast to the findings reported for Qdr2, CgQdr2 expression does not contribute to the ability of yeast to grow under K+-limiting conditions. Interestingly,CgQDR2transcript levels were seen to be upregulated inC. glabratacells challenged with clotrimazole or quinidine. This upregulation was found to depend directly on the transcription factor CgPdr1, the major regulator of multidrug resistance in this pathogenic yeast, which has also been found to be a determinant of quinidine and clotrimazole resistance inC. glabrata.

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The bZip Transcription Factor Cap1p Is Involved in Multidrug Resistance and Oxidative Stress Response inCandida albicans

Journal of Bacteriology ◽

10.1128/jb.181.3.700-708.1999 ◽

1999 ◽

Vol 181 (3) ◽

pp. 700-708 ◽

Cited By ~ 186

Author(s):

Anne-Marie Alarco ◽

Martine Raymond

Keyword(s):

Oxidative Stress ◽

Hydrogen Peroxide ◽

Transcription Factor ◽

Multidrug Resistance ◽

Stress Response ◽

Oxidative Stress Response ◽

Bzip Transcription Factor ◽

Term Therapy ◽

Pathogenic Yeast ◽

And Oxidative Stress

ABSTRACT Candida albicans is an opportunistic pathogenic yeast which frequently develops resistance to the antifungal agent fluconazole (FCZ) in patients undergoing long-term therapy. FCZ-resistant strains often display a reduced intracellular FCZ accumulation which correlates with the overexpression of the ATP-binding cassette transporters CDR1 and CDR2or the major facilitator (MF) MDR1. We have recently cloned a C. albicans gene, named CAP1, which codes for a bZip transcription factor of the AP-1 family homologous to the Yap1 protein involved in multidrug resistance and response to oxidative stress in Saccharomyces cerevisiae. CAP1 was found to confer FCZ resistance in S. cerevisiae by transcriptionally activating FLR1, a gene coding for an MF homologous to theC. albicans MDR1 gene product (A.-M. Alarco, I. Balan, D. Talibi, N. Mainville, and M. Raymond, J. Biol. Chem. 272:19304–19313, 1997). To study the role of CAP1 inC. albicans, we constructed a CAI4-derived mutant strain carrying a homozygous deletion of the CAP1 gene (CJD21). We found that deletion of CAP1 did not affect the susceptibility of CJD21 cells to FCZ, cerulenin, brefeldin A, and diamide but caused hypersensitivity to cadmium, 4-nitroquinolineN-oxide, 1,10-phenanthroline, and hydrogen peroxide, an effect which was reverted by reintroduction of the CAP1gene in these cells. Introduction of a hyperactive truncated allele ofCAP1 (CAP1-TR) in CJD21 resulted in resistance of the cells to all of the above compounds except hydrogen peroxide. The hyperresistant phenotype displayed by the CJD21 CAP1-TRtransformants was found to correlate with the overexpression of a number of potential CAP1 transcriptional targets such asMDR1, CaYCF1, CaGLR1, andCaTRR1. Taken together, our results demonstrate thatCAP1 is involved in multidrug resistance and oxidative stress response in C. albicans. Finally, disruption ofCAP1 in strain FR2, selected in vitro for FCZ resistance and constitutively overexpressing MDR1, did not suppress but rather increased the levels of MDR1 expression, demonstrating that CAP1 acts as a negative transcriptional regulator of the MDR1 gene in FR2 and is not responsible for MDR1 overexpression in this strain.

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Expression and Co-expression Analyses of WRKY, MYB, bHLH and bZIP Transcription Factor Genes in Potato (Solanum tuberosum) Under Abiotic Stress Conditions: RNA-seq Data Analysis

Potato Research ◽

10.1007/s11540-021-09502-3 ◽

2021 ◽

Author(s):

Ertugrul Filiz ◽

Firat Kurt

Keyword(s):

Transcription Factor ◽

Abiotic Stress ◽

Solanum Tuberosum ◽

Data Analysis ◽

Stress Conditions ◽

Bzip Transcription Factor ◽

Rna Seq ◽

Transcription Factor Genes

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A combinatorial action of GmMYB176 and GmbZIP5 controls isoflavonoid biosynthesis in soybean (Glycine max)

Communications Biology ◽

10.1038/s42003-021-01889-6 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Arun Kumaran Anguraj Vadivel ◽

Tim McDowell ◽

Justin B. Renaud ◽

Sangeeta Dhaubhadel

Keyword(s):

Transcription Factor ◽

Hairy Roots ◽

Defense Mechanisms ◽

Biosynthetic Pathway ◽

Bzip Transcription Factor ◽

Myb Transcription Factor ◽

In Planta ◽

Rnai Silencing ◽

Protein Protein Interaction ◽

Soybean Roots

AbstractGmMYB176 is an R1 MYB transcription factor that regulates multiple genes in the isoflavonoid biosynthetic pathway, thereby affecting their levels in soybean roots. While GmMYB176 is important for isoflavonoid synthesis, it is not sufficient for the function and requires additional cofactor(s). The aim of this study was to identify the GmMYB176 interactome for the regulation of isoflavonoid biosynthesis in soybean. Here, we demonstrate that a bZIP transcription factor GmbZIP5 co-immunoprecipitates with GmMYB176 and shows protein–protein interaction in planta. RNAi silencing of GmbZIP5 reduced the isoflavonoid level in soybean hairy roots. Furthermore, co-overexpression of GmMYB176 and GmbZIP5 enhanced the level of multiple isoflavonoid phytoallexins including glyceollin, isowighteone and a unique O-methylhydroxy isoflavone in soybean hairy roots. These findings could be utilized to develop biotechnological strategies to manipulate the metabolite levels either to enhance plant defense mechanisms or for human health benefits in soybean or other economically important crops.

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Molecular Mechanism of a Photoregulated bZIP Transcription Factor and Its Application as a Molecular Tool

Seibutsu Butsuri ◽

10.2142/biophys.54.307 ◽

2014 ◽

Vol 54 (6) ◽

pp. 307-310

Author(s):

Osamu HISATOMI

Keyword(s):

Transcription Factor ◽

Molecular Mechanism ◽

Bzip Transcription Factor ◽

Molecular Tool

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Interaction between optineurin and the bZIP transcription factor NRL

Cell Biology International ◽

10.1002/cbin.10174 ◽

2013 ◽

Vol 38 (1) ◽

pp. 16-25 ◽

Cited By ~ 4

Author(s):

Chunxia Wang ◽

Katsuhiro Hosono ◽

Masafumi Ohtsubo ◽

Kentaro Ohishi ◽

Jie Gao ◽

...

Keyword(s):

Transcription Factor ◽

Bzip Transcription Factor

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Increased Expression of Two Multidrug Transporter-Like Genes Is Associated with Ethidium Bromide and Ciprofloxacin Resistance in Mycoplasma hominis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.49.1.421-424.2005 ◽

2005 ◽

Vol 49 (1) ◽

pp. 421-424 ◽

Cited By ~ 16

Author(s):

S. Raherison ◽

P. Gonzalez ◽

H. Renaudin ◽

A. Charron ◽

C. Bébéar ◽

...

Keyword(s):

Multidrug Resistance ◽

Ethidium Bromide ◽

Reverse Transcription ◽

Mycoplasma Hominis ◽

Atp Binding ◽

Multidrug Transporter ◽

Reverse Transcription Pcr ◽

Atp Binding Cassette Transporters ◽

Resistant Strains ◽

Ciprofloxacin Resistance

ABSTRACT Two genes, md1 and md2, coding for multidrug resistance ATP-binding cassette transporters were identified in Mycoplasma hominis PG21. Expression of these two genes, quantified by quantitative competitive reverse transcription-PCR, was significantly increased in ethidium bromide-resistant strains of M. hominis compared to that in M. hominis PG21.

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