| Budget Amount *help |
¥3,302,000 (Direct Cost: ¥2,540,000、Indirect Cost: ¥762,000)
Fiscal Year 2009: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2008: ¥1,742,000 (Direct Cost: ¥1,340,000、Indirect Cost: ¥402,000)
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| Research Abstract |
MSI3 (multicopy suppressor of ira1 mutant, which causes hyperactivation of the Ras-cAMP-PKA pathway) was isolated as a gene involved in early yeast-hyphal transition of Candida albicans and is a novel member of the heat shock protein 70 family. Previously, we showed that MSI3 expression is quickly and significantly downregulated in N-acetyl-D-glucosamine (GlcNAc)-induced germination. We generated a mutant strain, tetMSI3, in which MSI3 is controlled under the tetracycline-regulatable promoter and we compared various phenotypes with those of the parent strain CAF2. Negative regulation of MSI3 expression with the tetracycline analog doxycycline resulted in a growth defect in tetMSI3 cells. In the absence of doxycycline, MSI3 expression was approximately 4-fold higher in tetMSI3 cells than in CAF2 cells in a growth medium, which increased the susceptibility to cell wall inhibitors. MSI3 expression was drastically reduced in response to GlcNAc in CAF2 cells. The results suggested that a drastic reduction in MSI3 expression by GlcNAc activates the Ras1-cAMP-PKA pathway, thus stimulating germination and also inducing resistance to hydrogen peroxide. Reduced expression and overexpression of MSI3 resulted in avirulence and attenuated virulence, respectively, in a murine model. Our findings suggest that C. albicans Msi3p has multiple functions in cell growth, cell wall integrity, negative regulation of hyphal morphogenesis via the Ras1-cAMP-PKA pathway, susceptibility to hydrogen peroxide, and virulence.
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