| Budget Amount *help |
¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2006: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2005: ¥2,900,000 (Direct Cost: ¥2,900,000)
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| Research Abstract |
LOH is one of the important steps for carcinogenesis. To monitor LOH induction, we constructed a system, which can detect LOH frequency as well as chromosome modification causing LOH in S. cerevisiae diploid cells. By using this system, we found that some non-mutagenic carcinogens induce LOH through chromosome loss (aneuploidy). Thus in this research project, we tried to 1) sensitize this assay system for screen such non-mutagenic carcinogens from our environment, 2) screen such non-mutagenic carcinogens, and 3) elucidate the mechanisms for induction of aneuploidy. We have observed that 11 non-mutagenic carcinogens among 24 chemicals tested were positive as LOH inducer through aneuploidy. For phenyl hydroquinone (PHQ) used as a model aneuploidy-inducible compound, we observed that 1) PHQ arrest cell cycle progression at G1 for G1 phase cells and at G2/M for S phase cells, 2) PHQ can interacts with tubulin proteins in vitro, 3) PHQ interferes tubulin depolymerization in vitro, 4) PHQ causes irregular elongation of spindle in G2/M arrested cells, and 5) PHQ inhibits Pds1 degradation at methaphase, indicating that PHQ block entering methaphase. Theses results indicate that some epigenetic mechanisms may be implicated in LOH induction through aneuploidy. Identification the target protein causing chromosome missegregation, followed by aneuploidy, may be an important clue for understanding carcinogenesis. These finding would also provide a important clue for chemical risk assessment.
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