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Research Paper |
Department of Medicine, Duke University Medical Center, Durham, NC, USA1
Department of Genetics, Duke University Medical Center, Durham, NC, USA2
Department of Microbiology, Duke University Medical Center, Durham, NC, USA3
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA4
Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC, USA5
Author for correspondence: J. Andrew Alspaugh. Tel:+1 919 684 2660. Fax: +1 919 684 5458. e-mail: andrew.alspaugh{at}duke.edu
The Ras1 signal transduction pathway controls the ability of the pathogenic fungus Cryptococcus neoformans to grow at high temperatures and to mate. A second RAS gene was identified in this organism. RAS2 is expressed at a very low level compared to RAS1, and a ras2 mutation caused no alterations in vegetative growth rate, differentiation or virulence factor expression. The ras2 mutant strain was equally virulent to the wild-type strain in the murine inhalational model of cryptococcosis. Although a ras1 ras2 double mutant strain is viable, mutation of both RAS genes results in a decreased growth rate at all temperatures compared to strains with either single mutation. Overexpression of the RAS2 gene completely suppressed the ras1 mutant mating defect and partially suppressed its high temperature growth defect. After prolonged incubation at a restrictive temperature, the ras1 mutant demonstrated actin polarity defects that were also partially suppressed by RAS2 overexpression. These studies indicate that the C. neoformans Ras1 and Ras2 proteins share overlapping functions, but also play distinct signalling roles. Our findings also suggest a mechanism by which Ras1 controls growth of this pathogenic fungus at 37 °C, supporting a conserved role for Ras homologues in microbial cellular differentiation, morphogenesis and virulence.
Keywords: microbial pathogenesis, fungi, yeast, actin, polarity
The GenBank accession number for the RAS2 sequence of C. neoformans H99 is AF294349.
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