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PDR5  -  ATP-binding cassette multidrug transporter...

Saccharomyces cerevisiae S288c

Synonyms: LEM1, Pleiotropic ABC efflux transporter of multiple drugs, Pleiotropic drug resistance protein 5, STS1, Suppressor of toxicity of sporidesmin, ...
 
 
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Disease relevance of PDR5

 

High impact information on PDR5

  • Furthermore, YDR1 overexpression impaired cell growth, an effect that could be rescued by overexpression of TBP [4].
  • The repressor complex is encoded by two essential genes, designated YDR1 and BUR6 [4].
  • We isolated a yeast mutant, lem1, with increased sensitivity to dexamethasone and triamcinolone acetonide; responsiveness to a third agonist, deoxycorticosterone, is unaffected [5].
  • We propose that transporters like LEM1 can selectively modulate the intracellular levels of steroid hormones [5].
  • Genetic analysis of the YDR1-BUR6 repressor complex reveals an intricate balance among transcriptional regulatory proteins in yeast [6].
 

Chemical compound and disease context of PDR5

 

Biological context of PDR5

  • Overexpression of Pdr13p leads to an increase in both the expression of PDR5 and YOR1 and a corresponding enhancement in drug resistance [12].
  • The yeast PDR5 gene encodes an efflux pump that confers multidrug resistance [13].
  • Loss of previously described nuclear-mitochondrial signaling genes like RTG1 reduce the level of PDR5 expression and drug resistance seen in rho(o) cells but has no effect on oxa1-induced phenotypes [14].
  • Disruption of both PDR5 and SNQ2 in a pdr1 mutant decreases the cell growth rate and reveals the presence of at least two other ATP binding cassette proteins in the 160-kDa overexpressed band that have been identified by amino-terminal microsequencing [15].
  • We have carried out a genetic screen to identify negative regulators of PDR5 expression and found that loss of the mitochondrial genome (rho(o) cells) causes up-regulation of Pdr3p but not Pdr1p function [14].
 

Anatomical context of PDR5

 

Associations of PDR5 with chemical compounds

  • The ATP binding cassette transporter-encoding genes regulated by Pdrlp include PDR5 and YOR1, which are required for normal cycloheximide and oligomycin tolerances, respectively [12].
  • The enzyme shows a nucleoside triphosphatase activity that differs biochemically from that of PDR5 (Decottignies, A., Kolaczkowski, M., Balzi, E., and Goffeau, A. (1994) J. Biol. Chem. 269, 12797-12803) and is sensitive to vanadate, erythrosine B, and Triton X-100 but not to oligomycin, which inhibits the PDR5 activity only [15].
  • Library deconvolution identified the 4-methoxy-2,3,6-trimethylbenzensulfonyl-substituted D-octapeptide KN20 as a potent Pdr5p ATPase inhibitor (concentration of drug causing 50% inhibition of enzyme activity [IC(50)], 4 microM) which chemosensitized AD/PDR5(+) to FLC, itraconazole, and ketoconazole [20].
  • Here, we show that PDR5 promoter activity is dramatically reduced when cells stop growing due to a limitation of glucose or nitrogen or when they approach stationary phase [21].
  • Although the protective role of TPO1 and PDR5 genes was confirmed, the majority of the responsive genes encoding multidrug resistance do not confer resistance to 2,4-D [22].
 

Physical interactions of PDR5

  • Loss of the mitochondrial genome (rho(0) cell) or elimination of the mitochondrial inner membrane protein Oxa1p causes a dramatic increase in expression of the ATP binding cassette transporter-encoding gene PDR5 in the yeast Saccharomyces cerevisiae [23].
  • Overexpression of the yeast Pdr5 ATP-binding cassette transporter leads to pleiotropic drug resistance to a variety of structurally unrelated cytotoxic compounds [24].
  • Interestingly, yeast Pdr5p interacted with flavonoids recently found to bind to cancer cell P-glycoprotein and to the protozoan parasite multidrug transporter [25].
 

Regulatory relationships of PDR5

  • However, the camptothecin resistance accompanying GAL1-promoted overexpression of PDR5 suggests some substrate promiscuity among the ATP-binding cassette transporters [26].
  • FDR-1 has been found to be an activated allele of the Pleiotropic Drug Resistance-1 (PDR-1) gene (termed PDR1-100) and to upregulate PDR5 transcription [17].
  • Pdr3p is involved in a retrograde response in which mitochondrial dysfunctions activate PDR5, a gene encoding an ABC membrane transporter [27].
  • A PDR5-independent pathway of multi-drug resistance regulated by the SIN4 gene product [28].
 

Other interactions of PDR5

  • Transcriptional control of the yeast PDR5 gene by the PDR3 gene product [29].
  • The PDR1 T879M mutant increased PDR5 transcription compared with wild-type PDR1 strains [26].
  • The ATP binding cassette transporters Pdr5 and Snq2 of Saccharomyces cerevisiae can mediate transport of steroids in vivo [1].
  • We also analyzed the interaction between PDR5 and YAP1 [30].
  • Zinc cluster protein Rdr1p is a transcriptional repressor of the PDR5 gene encoding a multidrug transporter [13].
 

Analytical, diagnostic and therapeutic context of PDR5

References

  1. The ATP binding cassette transporters Pdr5 and Snq2 of Saccharomyces cerevisiae can mediate transport of steroids in vivo. Mahé, Y., Lemoine, Y., Kuchler, K. J. Biol. Chem. (1996) [Pubmed]
  2. Loss of function mutation in the yeast multiple drug resistance gene PDR5 causes a reduction in chloramphenicol efflux. Leonard, P.J., Rathod, P.K., Golin, J. Antimicrob. Agents Chemother. (1994) [Pubmed]
  3. Multidrug resistance in Aspergillus nidulans involves novel ATP-binding cassette transporters. Del Sorbo, G., Andrade, A.C., Van Nistelrooy, J.G., Van Kan, J.A., Balzi, E., De Waard, M.A. Mol. Gen. Genet. (1997) [Pubmed]
  4. The Dr1/DRAP1 heterodimer is a global repressor of transcription in vivo. Kim, S., Na, J.G., Hampsey, M., Reinberg, D. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  5. LEM1, an ATP-binding-cassette transporter, selectively modulates the biological potency of steroid hormones. Kralli, A., Bohen, S.P., Yamamoto, K.R. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  6. Genetic analysis of the YDR1-BUR6 repressor complex reveals an intricate balance among transcriptional regulatory proteins in yeast. Kim, S., Cabane, K., Hampsey, M., Reinberg, D. Mol. Cell. Biol. (2000) [Pubmed]
  7. Pregnenolone esterification in Saccharomyces cerevisiae. A potential detoxification mechanism. Cauet, G., Degryse, E., Ledoux, C., Spagnoli, R., Achstetter, T. Eur. J. Biochem. (1999) [Pubmed]
  8. Interaction of the yeast pleiotropic drug resistance genes PDR1 and PDR5. Meyers, S., Schauer, W., Balzi, E., Wagner, M., Goffeau, A., Golin, J. Curr. Genet. (1992) [Pubmed]
  9. Cyclic AMP and fluconazole resistance in Saccharomyces cerevisiae. Kontoyiannis, D.P., Rupp, S. Antimicrob. Agents Chemother. (2000) [Pubmed]
  10. Enniatin has a new function as an inhibitor of Pdr5p, one of the ABC transporters in Saccharomyces cerevisiae. Hiraga, K., Yamamoto, S., Fukuda, H., Hamanaka, N., Oda, K. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  11. Saccharomyces cerevisiae YDR1, which encodes a member of the ATP-binding cassette (ABC) superfamily, is required for multidrug resistance. Hirata, D., Yano, K., Miyahara, K., Miyakawa, T. Curr. Genet. (1994) [Pubmed]
  12. Regulation of transcription factor Pdr1p function by an Hsp70 protein in Saccharomyces cerevisiae. Hallstrom, T.C., Katzmann, D.J., Torres, R.J., Sharp, W.J., Moye-Rowley, W.S. Mol. Cell. Biol. (1998) [Pubmed]
  13. Zinc cluster protein Rdr1p is a transcriptional repressor of the PDR5 gene encoding a multidrug transporter. Hellauer, K., Akache, B., MacPherson, S., Sirard, E., Turcotte, B. J. Biol. Chem. (2002) [Pubmed]
  14. Multiple signals from dysfunctional mitochondria activate the pleiotropic drug resistance pathway in Saccharomyces cerevisiae. Hallstrom, T.C., Moye-Rowley, W.S. J. Biol. Chem. (2000) [Pubmed]
  15. Identification and characterization of SNQ2, a new multidrug ATP binding cassette transporter of the yeast plasma membrane. Decottignies, A., Lambert, L., Catty, P., Degand, H., Epping, E.A., Moye-Rowley, W.S., Balzi, E., Goffeau, A. J. Biol. Chem. (1995) [Pubmed]
  16. Functional genomic analysis of fluconazole susceptibility in the pathogenic yeast Candida glabrata: roles of calcium signaling and mitochondria. Kaur, R., Castaño, I., Cormack, B.P. Antimicrob. Agents Chemother. (2004) [Pubmed]
  17. Efflux-mediated resistance to fluconazole could be modulated by sterol homeostasis in Saccharomyces cerevisiae. Kontoyiannis, D.P. J. Antimicrob. Chemother. (2000) [Pubmed]
  18. Two lepidopteran cell lines stably transformed by the abc transporter gene pdr5 show tolerance to diacetoxyscirpenol. Zhang, D.Y., Krell, P.J., Feng, Q.L. In Vitro Cell. Dev. Biol. Anim. (2006) [Pubmed]
  19. Endocytosis and vacuolar degradation of the plasma membrane-localized Pdr5 ATP-binding cassette multidrug transporter in Saccharomyces cerevisiae. Egner, R., Mahé, Y., Pandjaitan, R., Kuchler, K. Mol. Cell. Biol. (1995) [Pubmed]
  20. Chemosensitization of fluconazole resistance in Saccharomyces cerevisiae and pathogenic fungi by a D-octapeptide derivative. Niimi, K., Harding, D.R., Parshot, R., King, A., Lun, D.J., Decottignies, A., Niimi, M., Lin, S., Cannon, R.D., Goffeau, A., Monk, B.C. Antimicrob. Agents Chemother. (2004) [Pubmed]
  21. Expression regulation of the yeast PDR5 ATP-binding cassette (ABC) transporter suggests a role in cellular detoxification during the exponential growth phase. Mamnun, Y.M., Schüller, C., Kuchler, K. FEBS Lett. (2004) [Pubmed]
  22. Early transcriptional response of Saccharomyces cerevisiae to stress imposed by the herbicide 2,4-dichlorophenoxyacetic acid. Teixeira, M.C., Fernandes, A.R., Mira, N.P., Becker, J.D., Sá-Correia, I. FEMS Yeast Res. (2006) [Pubmed]
  23. Saccharomyces cerevisiae multidrug resistance gene expression inversely correlates with the status of the F(0) component of the mitochondrial ATPase. Zhang, X., Moye-Rowley, W.S. J. Biol. Chem. (2001) [Pubmed]
  24. Genetic separation of FK506 susceptibility and drug transport in the yeast Pdr5 ATP-binding cassette multidrug resistance transporter. Egner, R., Rosenthal, F.E., Kralli, A., Sanglard, D., Kuchler, K. Mol. Biol. Cell (1998) [Pubmed]
  25. Prenyl-flavonoids as potent inhibitors of the Pdr5p multidrug ABC transporter from Saccharomyces cerevisiae. Conseil, G., Decottignies, A., Jault, J.M., Comte, G., Barron, D., Goffeau, A., Di Pietro, A. Biochemistry (2000) [Pubmed]
  26. Camptothecin sensitivity is mediated by the pleiotropic drug resistance network in yeast. Reid, R.J., Kauh, E.A., Bjornsti, M.A. J. Biol. Chem. (1997) [Pubmed]
  27. Genome-wide studies on the nuclear PDR3-controlled response to mitochondrial dysfunction in yeast. Devaux, F., Carvajal, E., Moye-Rowley, S., Jacq, C. FEBS Lett. (2002) [Pubmed]
  28. A PDR5-independent pathway of multi-drug resistance regulated by the SIN4 gene product. Fleckenstein, A., Shallom, J., Golin, J. Yeast (1999) [Pubmed]
  29. Transcriptional control of the yeast PDR5 gene by the PDR3 gene product. Katzmann, D.J., Burnett, P.E., Golin, J., Mahé, Y., Moye-Rowley, W.S. Mol. Cell. Biol. (1994) [Pubmed]
  30. Mutations in the yeast PDR3, PDR4, PDR7 and PDR9 pleiotropic (multiple) drug resistance loci affect the transcript level of an ATP binding cassette transporter encoding gene, PDR5. Dexter, D., Moye-Rowley, W.S., Wu, A.L., Golin, J. Genetics (1994) [Pubmed]
  31. On the mechanism of constitutive Pdr1 activator-mediated PDR5 transcription in Saccharomyces cerevisiae: evidence for enhanced recruitment of coactivators and altered nucleosome structures. Gao, C., Wang, L., Milgrom, E., Shen, W.C. J. Biol. Chem. (2004) [Pubmed]
  32. A novel screening for inhibitors of a pleiotropic drug resistant pump, Pdr5, in Saccharomyces cerevisiae. Hiraga, K., Wanigasekera, A., Sugi, H., Hamanaka, N., Oda, K. Biosci. Biotechnol. Biochem. (2001) [Pubmed]
  33. A novel ATP-binding cassette transporter involved in multidrug resistance in the phytopathogenic fungus Penicillium digitatum. Nakaune, R., Adachi, K., Nawata, O., Tomiyama, M., Akutsu, K., Hibi, T. Appl. Environ. Microbiol. (1998) [Pubmed]
 
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