PDR16 and PDR17, Two Homologous Genes ofSaccharomyces cerevisiae, Affect Lipid Biosynthesis and Resistance to Multiple Drugs

Hazel, H. Bart van den; Pichler, Harald; Matta, Maria Adelaide do Valle; Leitner, Erich; Goffeau, André; Daum, Günther

doi:10.1074/jbc.274.4.1934

Cited by 148 publications

(125 citation statements)

References 58 publications

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“…In vegetative cells, two of these, Sfh2/Csr1p (Li et al, 2000;Santos and Snyder, 2000) and Sfh4/Pdr17p (van den Hazel et al, 1999;Li et al, 2000), potently suppress the sec14-1 lethality when overexpressed, and this suppression is dependent on Spo14p (Li et al, 2000). Likewise, these proteins suppressed the sec14-1 meiosis and spore-formation defects ( Table 2, lines 15 and 17), and the suppression of the meiotic defect was dependent on Spo14p function (Table 2, lines 16 and 18).…”

Section: Suppression Of Sec14 Sporulation Defect By Overexpression Ofmentioning

confidence: 92%

“…The BamHI-XhoI fragment containing the MSS4 gene from pYO1966 (Homma et al, 1998; generous gift of Yoshikazu Ohya, University of Tokyo, Tokyo, Japan) was moved into the BamHI and XhoI sites of pUN55 and YEp352 to generate pME2188 and pME1308, respectively. The ClaIϪ, whose ends had been filled in with the Klenow fragment of DNA polymerase, SacI fragment of PDR17/SFH4 from pBVH1402 (van den Hazel et al, 1999; generous gift of Maria Adelaide do Valle Matta, Universite Catholique de Louvain, Louvain-la-Neuve, Belgium), was moved into the SmaI and SacI sites of YEp352 to generate pME1854. YEp352 PIK1 (Flanagan et al, 1993), pGALHA-STT4 -8 (Cutler et al, 1997; generous gift of Maria Cardenas, Duke University Medical Center, Durham, NC), and YEp24-CSR1/SFH2 (Santos and Snyder, 2000; generous gift of Beatriz Santos, Universidad de Salamanca, Salamanca, Spain) are all described in detail in the references cited.…”

Section: Plasmidsmentioning

confidence: 99%

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Roles of Phosphoinositides and of Spo14p (phospholipase D)-generated Phosphatidic Acid during Yeast Sporulation

Rudge

Sciorra

Iwamoto

et al. 2004

MBoC

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During yeast sporulation, internal membrane synthesis ensures that each haploid nucleus is packaged into a spore. Prospore membrane formation requires Spo14p, a phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P 2 ]-stimulated phospholipase D (PLD), which hydrolyzes phosphatidylcholine (PtdCho) to phosphatidic acid (PtdOH) and choline. We found that both meiosis and spore formation also require the phosphatidylinositol (PtdIns)/PtdCho transport protein Sec14p. Specific ablation of the PtdIns transport activity of Sec14p was sufficient to impair spore formation but not meiosis. Overexpression of Pik1p, a PtdIns 4-kinase, suppressed the sec14-1 meiosis and spore formation defects; conversely, pik1-ts diploids failed to undergo meiosis and spore formation. The PtdIns(4)P 5-kinase, Mss4p, also is essential for spore formation. Use of phosphoinositide-specific GFP-PH domain reporters confirmed that PtdIns(4,5)P 2 is enriched in prospore membranes. sec14, pik1, and mss4 mutants displayed decreased Spo14p PLD activity, whereas absence of Spo14p did not affect phosphoinositide levels in vivo, suggesting that formation of PtdIns(4,5)P 2 is important for Spo14p activity. Spo14p-generated PtdOH appears to have an essential role in sporulation, because treatment of cells with 1-butanol, which supports Spo14p-catalyzed PtdCho breakdown but leads to production of Cho and Ptd-butanol, blocks spore formation at concentrations where the inert isomer, 2-butanol, has little effect. Thus, rather than a role for PtdOH in stimulating PtdIns(4,5)P 2 formation, our findings indicate that during sporulation, Spo14p-mediated PtdOH production functions downstream of Sec14p-, Pik1p-, and Mss4p-dependent PtdIns(4,5)P 2 synthesis.

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Section: Suppression Of Sec14 Sporulation Defect By Overexpression Ofmentioning

confidence: 92%

Section: Plasmidsmentioning

confidence: 99%

Roles of Phosphoinositides and of Spo14p (phospholipase D)-generated Phosphatidic Acid during Yeast Sporulation

Rudge

Sciorra

Iwamoto

et al. 2004

MBoC

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“…cerevisiae, deletion of ERG6 increases the rate of passive diffusion of small lipophilic drugs (Emter et al, 2002). Budding yeast cells lacking Pdr16p and Pdr17p have altered membrane sterol and lipid composition, display increased rates of passive drug diffusion, and are hypersensitive to many drugs (van den Hazel et al, 1999). The CPY colony blot assay indicated that cell integrity might be reduced in erg2D and erg6D cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

Multiple functions of ergosterol in the fission yeast Schizosaccharomyces pombe

et al. 2008

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Sterols are a major class of membrane lipids in eukaryotes. In Schizosaccharomyces pombe, sterol 24-C-methyltransferase (Erg6p), C-8 sterol isomerase (Erg2p), C-5 sterol desaturase (Erg31p, Erg32p), C-22 sterol desaturase (Erg5p) and C-24 (28) sterol reductase (Sts1p/ Erg4p) have been predicted, but not yet determined, to catalyse a sequence of reactions from zymosterol to ergosterol. Disruption mutants of these genes were unable to synthesize ergosterol, and most were tolerant to the polyene drugs amphotericin B and nystatin. Disruption of erg31 + or erg32 + did not cause ergosterol deficiency or tolerance to polyene drugs, indicating that the two C-5 sterol desaturases have overlapping functions. GFP-tagged DRM (detergent-resistant membrane)-associated protein Pma1p localized to the plasma membrane in ergD mutants. DRM fractionation revealed that the association between Pma1-GFP and DRM was weakened in erg6D but not in other erg mutants. Several GFP-tagged plasma membrane proteins were tested, and an amino acid permease homologue, SPBC359.03c, was found to mislocalize to intracellular punctate structures in the ergD mutants. These results indicate that these proteins are responsible for ergosterol biosynthesis in fission yeast, similar to the situation in Saccharomyces cerevisiae. Furthermore, in fission yeast, ergosterol is important for plasma membrane structure and function and for localization of plasma membrane proteins. INTRODUCTIONSterols are essential structural and regulatory components of eukaryotic cell membranes. Mammals, plants and fungi produce similar sterols, which differ in the number and location of double bonds and methyl side chains. Ergosterol is the end product of the sterol biosynthetic pathway and is the major sterol in yeasts (Fig. 1a). Like cholesterol in mammalian cells, it is responsible for membrane fluidity and permeability (Parks et al., 1995).Ergosterol synthesis and metabolism have been well defined in the budding yeast Saccharomyces cerevisiae (Daum et al., 1998). Multiple genetic and biochemical studies have culminated in the virtually complete elucidation of the pathway leading to ergosterol (Lees et al., 1995;Parks et al., 1995). The enzymic reactions have been largely defined by identification of erg mutants defective in ergosterol biosynthesis, and by their complementation based on sterol auxotrophy or altered sterol composition. Most genes involved in the early part of the pathway to lanosterol are essential for growth, because yeasts require sterols and no sterol molecule is synthesized up to this point. In contrast, mutations in the steps from zymosterol to ergosterol (Fig. 1b) are not essential for growth because the intermediates produced can partially substitute for ergosterol. The latter part of the ergosterol biosynthetic pathway is not linear in the sense of consecutive reactions, because the enzymes converting lanosterol to ergosterol do not show a strict substrate preference. Thus, null mutants impaired in the steps from zymosterol to ergosterol accumulate char...

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“…Cell wall isolation and ␤-glucan was measured as described previously (32). van den Hazel's protocol for Rhodamine-6G uptake assay was used (33).…”

Section: Methodsmentioning

confidence: 99%

The Rho1 GTPase-activating Protein CgBem2 Is Required for Survival of Azole Stress in Candida glabrata

Borah¹,

Shivarathri

Kaur

2011

Journal of Biological Chemistry

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Invasive fungal infections are common clinical complications of neonates, critically ill, and immunocompromised patients worldwide. Candida species are the leading cause of disseminated fungal infections, with Candida albicans being the most prevalent species. Candida glabrata, the second/third most common cause of candidemia, shows reduced susceptibility to a widely used antifungal drug fluconazole. Here, we present findings from a screen of 9134 C. glabrata Tn7 insertion mutants for altered survival profiles in the presence of fluconazole. We have identified two components of RNA polymerase II mediator complex, three players of Rho GTPase-mediated signaling cascade, and two proteins implicated in actin cytoskeleton biogenesis and ergosterol biosynthesis that are required to sustain viability during fluconazole stress. We show that exposure to fluconazole leads to activation of the protein kinase C (PKC)-mediated cell wall integrity pathway in C. glabrata. Our data demonstrate that disruption of a RhoGAP (GTPase activating protein) domain-containing protein, CgBem2, results in budemergence defects, azole susceptibility, and constitutive activation of CgRho1-regulated CgPkc1 signaling cascade and cell wall-related phenotypes. The viability loss of Cgbem2⌬ mutant upon fluconazole treatment could be partially rescued by the PKC inhibitor staurosporine. Additionally, we present evidence that CgBEM2 is required for the transcriptional activation of genes encoding multidrug efflux pumps in response to fluconazole exposure. Last, we report that Hsp90 inhibitor geldanamycin renders fluconazole a fungicidal drug in C. glabrata.

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PDR16 and PDR17, Two Homologous Genes ofSaccharomyces cerevisiae, Affect Lipid Biosynthesis and Resistance to Multiple Drugs

Cited by 148 publications

References 58 publications

Roles of Phosphoinositides and of Spo14p (phospholipase D)-generated Phosphatidic Acid during Yeast Sporulation

Roles of Phosphoinositides and of Spo14p (phospholipase D)-generated Phosphatidic Acid during Yeast Sporulation

Multiple functions of ergosterol in the fission yeast Schizosaccharomyces pombe

The Rho1 GTPase-activating Protein CgBem2 Is Required for Survival of Azole Stress in Candida glabrata

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