SRE1 and SRE2 are two specific steroid‐responsive modules of <i>Candida</i> drug resistance gene 1 (<i>CDR1</i>) promoter

Karnani, Neerja; Gaur, Naseem A.; Jha, Sudhakar; Puri, Niti; Krishnamurthy, Shankarling; Goswami, Shyamal; Mukhopadhyay, Gauranga; Prasad, Rajendra

doi:10.1002/yea.1067

Cited by 50 publications

(44 citation statements)

References 49 publications

(75 reference statements)

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“…Since the hyphal form is responsible for tissue invasion, these reports imply that steroid hormones could act as cues for the virulence of C. albicans. The steroid signaling pathways are largely unknown in Candida, though steroid binding proteins exist in C. albicans (49). It was also observed that brief exposure of Candida cells to steroid hormones results in upregulation of the CDR1 gene (50).…”

Section: Cdr1p Transports Unconventional Moleculesmentioning

confidence: 99%

“…Since human steroid hormones induce CDR1 expression, its promoter was examined for the presence of steroid-responsive elements. The search resulted in the identification of a steroid-responsive region (SRR) comprising two distinct cis elements, SRE1 and SRE2, responsive to progesterone and progesterone and ␤-estradiol, respectively (49). Transcriptional analysis of Candida cells upon exposure to estrogen show the upregulation of CDR1 and CDR2, indicating a plausible connection with drug resistance (48).…”

Section: Regulation Of Cdr1 Transcriptionmentioning

confidence: 99%

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The ABCs of Candida albicans Multidrug Transporter Cdr1

et al. 2015

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bIn the light of multidrug resistance (MDR) among pathogenic microbes and cancer cells, membrane transporters have gained profound clinical significance. Chemotherapeutic failure, by far, has been attributed mainly to the robust and diverse array of these proteins, which are omnipresent in every stratum of the living world. Candida albicans, one of the major fungal pathogens affecting immunocompromised patients, also develops MDR during the course of chemotherapy. The pivotal membrane transporters that C. albicans has exploited as one of the strategies to develop MDR belongs to either the ATP binding cassette (ABC) or the major facilitator superfamily (MFS) class of proteins. The ABC transporter Candida drug resistance 1 protein (Cdr1p) is a major player among these transporters that enables the pathogen to outplay the battery of antifungals encountered by it. The promiscuous Cdr1 protein fulfills the quintessential need of a model to study molecular mechanisms of multidrug transporter regulation and structure-function analyses of asymmetric ABC transporters. In this review, we cover the highlights of two decades of research on Cdr1p that has provided a platform to study its structure-function relationships and regulatory circuitry for a better understanding of MDR not only in yeast but also in other organisms.

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Section: Cdr1p Transports Unconventional Moleculesmentioning

confidence: 99%

Section: Regulation Of Cdr1 Transcriptionmentioning

confidence: 99%

The ABCs of Candida albicans Multidrug Transporter Cdr1

et al. 2015

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“…In addition, another BRE (located between ÿ243 and ÿ234) and a 1 negative regulatory element (NRE) located within the ÿ289 region have been reported in CDR1 (Puri et al 1999;Gaur et al 2004). Finally, in the same gene, Karnani et al (2004) identified SRE1 and SRE2 (steroid response elements) between ÿ696 and ÿ521.…”

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confidence: 90%

A Mutation in Tac1p, a Transcription Factor Regulating CDR1 and CDR2, Is Coupled With Loss of Heterozygosity at Chromosome 5 to Mediate Antifungal Resistance in Candida albicans

Coste¹,

Turner²,

Ischer³

et al. 2006

Genetics

343

359

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TAC1, a Candida albicans transcription factor situated near the mating-type locus on chromosome 5, is necessary for the upregulation of the ABC-transporter genes CDR1 and CDR2, which mediate azole resistance. We showed previously the existence of both wild-type and hyperactive TAC1 alleles. Wild-type alleles mediate upregulation of CDR1 and CDR2 upon exposure to inducers such as fluphenazine, while hyperactive alleles result in constitutive high expression of CDR1 and CDR2. Here we recovered TAC1 alleles from two pairs of matched azole-susceptible (DSY294; FH1: heterozygous at mating-type locus) and azole-resistant isolates (DSY296; FH3: homozygous at mating-type locus). Two different TAC1 wild-type alleles were recovered from DSY294 (TAC1-3 and TAC1-4) while a single hyperactive allele (TAC1-5) was isolated from DSY296. A single amino acid (aa) difference between TAC1-4 and TAC1-5 (Asn977 to Asp or N977D) was observed in a region corresponding to the predicted activation domain of Tac1p. Two TAC1 alleles were recovered from FH1 (TAC1-6 and TAC1-7) and a single hyperactive allele (TAC1-7) was recovered from FH3. The N977D change was seen in TAC1-7 in addition to several other aa differences. The importance of N977D in conferring hyperactivity to TAC1 was confirmed by site-directed mutagenesis. Both hyperactive alleles TAC1-5 and TAC1-7 were codominant with wild-type alleles and conferred hyperactive phenotypes only when homozygous. The mechanisms by which hyperactive alleles become homozygous was addressed by comparative genome hybridization and single nucleotide polymorphism arrays and indicated that loss of TAC1 heterozygosity can occur by recombination between portions of chromosome 5 or by chromosome 5 duplication. C ANDIDA albicans is an opportunistic pathogen that causes oral and systemic infections in immunocompromised patients as well as vaginal infections in immunocompetent women. To prevent and treat Candida infections, immunocompromised patients are often treated for a long time with antifungal agents among which is the class of azoles. As azoles are fungistatic, rather than fungicidal, C. albicans cells repetitively exposed to these antifungals can adapt to the drug pressure and eventually become resistant to azoles. The most important mechanism of resistance to azoles is the overexpression of multidrug transporters, encoded by either the major facilitator efflux pump CaMDR1 (multidrug resistance 1) or the ABC transporters CDR1 (candida drug resistance) and CDR2. Upregulation of CaMDR1 confers resistance to fluconazole, while upregulation of CDR1 and CDR2 confers resistance to multiple azoles (itraconazole, fluconazole, voriconazole). Understanding the transcriptional control of these genes, by both cis-and trans-acting effectors, is therefore important for determining how azole resistance and transport mechanisms are regulated in C. albicans.CaMDR1 expression is controlled by at least two regulatory promoter cis-acting regions as reported recently by Harry et al. (2005). Several elements of...

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“…RNA was stored at Ϫ80°C until use. [18][19][20][21] ] (Eurogentec), 3 l of 6.67 mM deoxynucleoside triphosphates (Roche), 1 l of 1 mM dCTP (Roche), 1.5 l of 1 mM cyanine 3 (Cy3)-dCTP or 1.5 l of 1 mM cyanine 5(Cy5)-dCTP (Amersham Biosciences), 4 l of 100 mM DTT (Invitrogen), 1 l of RNasin (20 to 40 U/l; Promega, Wallisellen, Switzerland), and diethyl pyrocarbonate-treated water to a volume of 40 l. The mixture was heated at 65°C for 5 min and cooled at 42°C for 5 min. The reverse transcription reaction was performed for 1 h at 42°C with 1 l of RNasin and 200 U of SuperScript II reverse transcriptase (Invitrogen).…”

Section: Tac1mentioning

confidence: 99%

TAC1 , Transcriptional Activator of CDR Genes, Is a New Transcription Factor Involved in the Regulation of Candida albicans ABC Transporters CDR1 and CDR2

Coste¹,

Karababa²,

Ischer³

et al. 2004

Eukaryot Cell

372

388

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The ABC transporter genes CDR1 and CDR2 can be upregulated in Candida albicans developing resistance to azoles or can be upregulated by exposing cells transiently to drugs such as fluphenazine. The cis-acting drug-responsive element (DRE) present in the promoters of both genes and necessary for their upregulation contains 5-CGG-3 triplets that are often recognized by transcriptional activators with Zn(2)-Cys(6) fingers. In order to isolate regulators of CDR1 and CDR2, the C. albicans genome was searched for genes encoding proteins with Zn(2)-Cys(6) fingers. Interestingly, three of these genes were tandemly arranged near the mating locus. Their involvement in CDR1 and CDR2 upregulation was addressed because a previous study demonstrated a link between mating locus homozygosity and azole resistance. The deletion of only one of these genes (orf19.3188) was sufficient to result in a loss of transient CDR1 and CDR2 upregulation by fluphenazine and was therefore named TAC1 (transcriptional activator of CDR genes). Tac1p has a nuclear localization, and a fusion of Tac1p with glutathione S-transferase could bind the cis-acting regulatory DRE in both the CDR1 and the CDR2 promoters. TAC1 is also relevant for azole resistance, since a TAC1 allele (TAC1-2) recovered from an azole-resistant strain could trigger constitutive upregulation of CDR1 and CDR2 in an azole-susceptible laboratory strain. Transcript profiling experiments performed with a TAC1 mutant and a revertant containing TAC1-2 revealed not only CDR1 and CDR2 as targets of TAC1 regulation but also other genes (RTA3, IFU5, and HSP12) that interestingly contained a DRE-like element in their promoters. In conclusion, TAC1 appears to be the first C. albicans transcription factor involved in the control of genes mediating antifungal resistance.

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SRE1 and SRE2 are two specific steroid‐responsive modules of Candida drug resistance gene 1 (CDR1) promoter

Cited by 50 publications

References 49 publications

The ABCs of Candida albicans Multidrug Transporter Cdr1

The ABCs of Candida albicans Multidrug Transporter Cdr1

A Mutation in Tac1p, a Transcription Factor Regulating CDR1 and CDR2, Is Coupled With Loss of Heterozygosity at Chromosome 5 to Mediate Antifungal Resistance in Candida albicans

TAC1 , Transcriptional Activator of CDR Genes, Is a New Transcription Factor Involved in the Regulation of Candida albicans ABC Transporters CDR1 and CDR2

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