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• W2045507047 endingPage "e1001069" @default.
• W2045507047 startingPage "e1001069" @default.
• W2045507047 abstract "Fungal pathogens exploit diverse mechanisms to survive exposure to antifungal drugs. This poses concern given the limited number of clinically useful antifungals and the growing population of immunocompromised individuals vulnerable to life-threatening fungal infection. To identify molecules that abrogate resistance to the most widely deployed class of antifungals, the azoles, we conducted a screen of 1,280 pharmacologically active compounds. Three out of seven hits that abolished azole resistance of a resistant mutant of the model yeast Saccharomyces cerevisiae and a clinical isolate of the leading human fungal pathogen Candida albicans were inhibitors of protein kinase C (PKC), which regulates cell wall integrity during growth, morphogenesis, and response to cell wall stress. Pharmacological or genetic impairment of Pkc1 conferred hypersensitivity to multiple drugs that target synthesis of the key cell membrane sterol ergosterol, including azoles, allylamines, and morpholines. Pkc1 enabled survival of cell membrane stress at least in part via the mitogen activated protein kinase (MAPK) cascade in both species, though through distinct downstream effectors. Strikingly, inhibition of Pkc1 phenocopied inhibition of the molecular chaperone Hsp90 or its client protein calcineurin. PKC signaling was required for calcineurin activation in response to drug exposure in S. cerevisiae. In contrast, Pkc1 and calcineurin independently regulate drug resistance via a common target in C. albicans. We identified an additional level of regulatory control in the C. albicans circuitry linking PKC signaling, Hsp90, and calcineurin as genetic reduction of Hsp90 led to depletion of the terminal MAPK, Mkc1. Deletion of C. albicans PKC1 rendered fungistatic ergosterol biosynthesis inhibitors fungicidal and attenuated virulence in a murine model of systemic candidiasis. This work establishes a new role for PKC signaling in drug resistance, novel circuitry through which Hsp90 regulates drug resistance, and that targeting stress response signaling provides a promising strategy for treating life-threatening fungal infections." @default.
• W2045507047 created "2016-06-24" @default.
• W2045507047 creator A5000151697 @default.
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• W2045507047 date "2010-08-26" @default.
• W2045507047 modified "2023-10-01" @default.
• W2045507047 title "PKC Signaling Regulates Drug Resistance of the Fungal Pathogen Candida albicans via Circuitry Comprised of Mkc1, Calcineurin, and Hsp90" @default.
• W2045507047 cites W1557800963 @default.
• W2045507047 cites W1596996692 @default.
• W2045507047 cites W1967864456 @default.
• W2045507047 cites W1968208372 @default.
• W2045507047 cites W1972736746 @default.
• W2045507047 cites W1972770043 @default.
• W2045507047 cites W1974145667 @default.
• W2045507047 cites W1978970152 @default.
• W2045507047 cites W1979749196 @default.
• W2045507047 cites W1980814667 @default.
• W2045507047 cites W1981118509 @default.
• W2045507047 cites W1988825409 @default.
• W2045507047 cites W1988874714 @default.
• W2045507047 cites W1993525477 @default.
• W2045507047 cites W1994548351 @default.
• W2045507047 cites W1995380559 @default.
• W2045507047 cites W2006754735 @default.
• W2045507047 cites W2009485798 @default.
• W2045507047 cites W2012050459 @default.
• W2045507047 cites W2018134501 @default.
• W2045507047 cites W2021593763 @default.
• W2045507047 cites W2022326366 @default.
• W2045507047 cites W2029979826 @default.
• W2045507047 cites W2034733986 @default.
• W2045507047 cites W2038204439 @default.
• W2045507047 cites W2039634851 @default.
• W2045507047 cites W2041611856 @default.
• W2045507047 cites W2042092509 @default.
• W2045507047 cites W2051744311 @default.
• W2045507047 cites W2054994755 @default.
• W2045507047 cites W2064787601 @default.
• W2045507047 cites W2065220166 @default.
• W2045507047 cites W2075525586 @default.
• W2045507047 cites W2079122560 @default.
• W2045507047 cites W2080229333 @default.
• W2045507047 cites W2081581252 @default.
• W2045507047 cites W2082568641 @default.
• W2045507047 cites W2084559668 @default.
• W2045507047 cites W2084577762 @default.
• W2045507047 cites W2085547973 @default.
• W2045507047 cites W2087273774 @default.
• W2045507047 cites W2091601808 @default.
• W2045507047 cites W2098563304 @default.
• W2045507047 cites W2105638437 @default.
• W2045507047 cites W2106031809 @default.
• W2045507047 cites W2106835772 @default.
• W2045507047 cites W2107013040 @default.
• W2045507047 cites W2115172705 @default.
• W2045507047 cites W2119811365 @default.
• W2045507047 cites W2121972996 @default.
• W2045507047 cites W2122446900 @default.
• W2045507047 cites W2123653303 @default.
• W2045507047 cites W2126656381 @default.
• W2045507047 cites W2129004089 @default.
• W2045507047 cites W2129227816 @default.
• W2045507047 cites W2131817226 @default.
• W2045507047 cites W2132919995 @default.
• W2045507047 cites W2135342672 @default.
• W2045507047 cites W2136493024 @default.
• W2045507047 cites W2138281171 @default.
• W2045507047 cites W2138767066 @default.
• W2045507047 cites W2138910991 @default.
• W2045507047 cites W2141563676 @default.
• W2045507047 cites W2143154997 @default.
• W2045507047 cites W2146558016 @default.
• W2045507047 cites W2147289133 @default.
• W2045507047 cites W2148652865 @default.
• W2045507047 cites W2149198831 @default.
• W2045507047 cites W2150492289 @default.
• W2045507047 cites W2154051597 @default.
• W2045507047 cites W2156217754 @default.
• W2045507047 cites W2157937554 @default.
• W2045507047 cites W2158005927 @default.
• W2045507047 cites W2158797036 @default.
• W2045507047 cites W2159718078 @default.
• W2045507047 cites W2160588674 @default.
• W2045507047 cites W2164215880 @default.
• W2045507047 cites W2167502710 @default.
• W2045507047 cites W2167944112 @default.
• W2045507047 cites W2171411897 @default.
• W2045507047 cites W2175029576 @default.
• W2045507047 doi "https://doi.org/10.1371/journal.ppat.1001069" @default.
• W2045507047 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/2928802" @default.
• W2045507047 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/20865172" @default.
• W2045507047 hasPublicationYear "2010" @default.

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