Resistance to diverse drugs and ultraviolet light conferred by overexpression of a novel human 26 S proteasome subunit.
We have investigated the usefulness of the fission yeast Schizosaccharomyces pombe as a model organism for the discovery of novel modes of drug resistance in human cells. In fission yeast, overexpression of the essential pad1(+) gene confers pleiotropic drug resistance through a pathway involving an AP-1 transcription factor encoded by pap1(+). We have identified POH1, a human pad1 homologue that can substitute fully for pad1(+) and induce AP-1-dependent drug resistance in fission yeast. POH1 also confers P-glycoprotein-independent resistance to taxol (paclitaxel), doxorubicin, 7-hydroxystaurosporine, and ultraviolet light when transiently overexpressed in mammalian cells. Poh1 is a previously unidentified component of the human 26 S proteasome, a multiprotein complex that degrades proteins targeted for destruction by the ubiquitin pathway. Hence, Poh1 is part of a conserved mechanism that determines cellular susceptibility to cytotoxic agents, perhaps by influencing the ubiquitin-dependent proteolysis of transcription factors.
Spataro
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Imperial Cancer Research Fund Molecular Oncology Laboratory, University of Oxford Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom.
Toda
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Craig
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Seeger
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Dubiel
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Harris
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Norbury
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D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D003001:Cloning, Molecular; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000502:physiology*; D004317:Doxorubicin / Q000378:metabolism; D018432:Drug Resistance, Multiple; D005800:Genes, Fungal; D006801:Humans; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000737:chemistry / Q000502:physiology*; D000073718:Pancreatitis-Associated Proteins; D046988:Proteasome Endopeptidase Complex; D012568:Schizosaccharomyces / Q000235:genetics*; D029702:Schizosaccharomyces pombe Proteins; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015534:Trans-Activators / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000502:physiology*
D009097:Multienzyme Complexes; C109285:PSMD14 protein, human; D000073718:Pancreatitis-Associated Proteins; C000612141:REG3A protein, human; D029702:Schizosaccharomyces pombe Proteins; D015534:Trans-Activators; D018808:Transcription Factor AP-1; C093857:rpn11 protein, S pombe; D004317:Doxorubicin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex