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In a genome-wide functional screen in the yeast <jats:italic>Saccharomyces cerevisiae,<\/jats:italic> inactivation of <jats:italic>IRA2<\/jats:italic>, a yeast ortholog of the human tumor suppressor gene <jats:italic>NF1<\/jats:italic> (Neurofibromin), enhanced sensitivity to hydroquinone, an important benzene metabolite. Increased Ras signaling is implicated as a causal factor in the increased pre-disposition to leukemia of individuals with mutations in <jats:italic>NF1<\/jats:italic>.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>Growth inhibition of yeast by hydroquinone was assessed in mutant strains exhibiting varying levels of Ras activity. Subsequently, effects of hydroquinone on both genotoxicity (measured by micronucleus formation) and proliferation of WT and <jats:italic>Nf1<\/jats:italic> null murine hematopoietic precursors were assessed.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Here we show that the Ras status of both yeast and mammalian cells modulates hydroquinone toxicity, indicating potential synergy between Ras signaling and benzene toxicity. Specifically, enhanced Ras signaling increases both hydroquinone-mediated growth inhibition in yeast and genotoxicity in mammalian hematopoetic precursors as measured by an <jats:italic>in vitro<\/jats:italic> erythroid micronucleus assay. Hydroquinone also increases proliferation of CFU-GM progenitor cells in mice with <jats:italic>Nf1<\/jats:italic> null bone marrow relative to WT, the same cell type associated with benzene-associated leukemia.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>Together our findings show that hydroquinone toxicity is modulated by Ras signaling. Individuals with abnormal Ras signaling could be more vulnerable to developing myeloid diseases after exposure to benzene. We note that hydroquinone is used cosmetically as a skin-bleaching agent, including by individuals with cafe-au-lait spots (which may be present in individuals with neurofibromatosis who have a mutation in <jats:italic>NF1<\/jats:italic>), which could be unadvisable given our findings.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1471-2407-14-6","type":"journal-article","created":{"date-parts":[[2014,1,5]],"date-time":"2014-01-05T02:01:05Z","timestamp":1388887265000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Modulation of Ras signaling alters the toxicity of hydroquinone, a benzene metabolite and component of cigarette smoke"],"prefix":"10.1186","volume":"14","author":[{"given":"Matthew","family":"North","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joe","family":"Shuga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Fromowitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre","family":"Loguinov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Shannon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luoping","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martyn T","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris D","family":"Vulpe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2014,1,5]]},"reference":[{"key":"4250_CR1","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1146\/annurev.publhealth.012809.103646","volume":"31","author":"MT Smith","year":"2010","unstructured":"Smith MT: Advances in understanding benzene health effects and susceptibility. 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