| Co-Investigator(Kenkyū-buntansha) |
FUJIWARA Tazuko OKAYAMA UNIV., MEDICAL SCHOOL, Research Associate, 医学部, 助手 (70108166)
ODA Megumi OKAYAMA UNIV., MEDICAL SCHOOL, Professor, 医学部, 教授 (50160875)
OUCHIDA Mamoru OKAYAMA UNIV., MEDICAL SCHOOL, Associate Professor, 医学部, 助教授 (80213635)
KAKU Shunkou OKAYAMA UNIV., HOSPITAL, Medical Associate, 医学部・附属病院, 医員
SAKAI Akiko OKAYAMA UNIV., MEDICAL SCHOOL, Research Associate, 医学部, 助手 (60205698)
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| Budget Amount *help |
¥5,700,000 (Direct Cost: ¥5,700,000)
Fiscal Year 2000: ¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 1999: ¥2,900,000 (Direct Cost: ¥2,900,000)
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| Research Abstract |
We have found a novel tumor-specific mutation in the gene encoding E2F4 transcription regulator in a subset of genetically unstable (MI+) colorectal cancers in 1996. The mutation was found to be a result of the inactivating frame-shift mutation of the hMSH3 gene, a DNA mismatch-repair gene. Thus, the E2F4 gene was identified, for the first time, as a target of the defective mismatch repair function involving hMSH3 protein. This notion has been confirmed bv many supporting papers. Relevant to this result, we have found an interstitial deletion within the human p107 gene, a close relative of the tumor suppressor gene RB, in a diffuse-large B cell lymphoma cell line. We found the deletion was raised by a recombination between two Alu-repeats encompassing about 15 kbp. By our genomic scanning method, we found a novel region of loss of heterozygosity (LOH) at chromosome 14q24-31 in about 30% of renal cell carcinomas and identified two candidate tumor suppressor genes (TSG) in this narrow re
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gion. By conventional microsatellite analysis, we found a high incidence of LOH at chromosome 13q34 in human head and neck cancers. The known candidate TSG, ING1, resides at this site. We clarified the whole genomic structure of the ING1 gene and found 3 inactivating point mutations in 3 primary head and neck cancers with 13q34 LOH.These are the first evidence indicatins that the p107 and ING1 genes function as TSG.Further, we discovered a novel protein tyrosine-phosphatase gene, HD-PTP, as a novel TSG candidate. The gene resides at chromosome 3p21.3, the region thought to contain multiple TSG for many types of human cancer. By similar approaches we found at least 10 TSG candidates at 8 chromosomal regions in 7 cancer/tumor groups. In addition to TSG, we isolated a cDNA encoding a novel POZ-Zn-Finger protein, whose expression led the recipient cells to malignant phenotype, suggesting that the gene is a novel oncogene. The gene locates on 3q26-27 and related to the known oncogene, Bcl-6.
As to the molecular diagnosis of cancer, we reported a systematic method for detecting tumor-specific, fused-gene mRNAs in several bone/soft-tissue sarcomas. We have developed a new strategy to quantitate the amounts of free DNA in sera/plasma with a very high sensitivity (about ten thousand-fold higher than conventional methods). Cancer-specific genetic alterations, like as K-ras and p53 mutations, could be detected in these serum-DNA.Thus, promising strategies for early detection of potential cancer-patients were developed with free DNA in plasma/serum. Less
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