| Co-Investigator(Kenkyū-buntansha) |
YAMADA Taketo Keio University, School of Medicine, Dept. of Pathol, Assistant professor, 医学部, 専任講師 (60230463)
UMEZAWA Akihiro Keio University, School of Medicine, Dept. of Pathol, Associate professor, 医学部, 助教授 (70213486)
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| Research Abstract |
We performed molecular pathological analysis of embryonal tumors such as germ cell tumors, Wilms tumors and Ewing/PNET tumors which are thought to be derived from embryonal tissue during.
1, we originally isolated EAT (early gene induced by all trans retinoic acid) gene from embryonal carcinoma cell lines (NCR-G3). Sequencing analysis revealed that EAT possessed BH1 and BH2 domains suggesting a bcl family gene. This gene was shown to have antiapoptotic functions by vitro and in vivo studies. Northern analysis and immunohistochemical studies disclosed that he EAT gene distributed in a variety of fetal and adult tissues including stage of early embryogenesis. EAT gene was shown to exclusively localize in the external and internal membrane of mitochondria by using immunoelectron microscopic procedures. These findings suggested that this gene play an important role in maintenance of early embryogenesis through antiapoptotic functions.
2, Wilms tumor are a typical embryonal tumors that is der
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ived from metanephric blastoma and the most common renal tumors in childhood. Novel gene, WT1, has been isolated chromosome11p13 region as a responsible gene in oncogenesis of Wilms tumor. This gene also play an important role in normal nephrogenesis and gonadal developments, especially male genital organs. Denys-Drash syndrome characterized by association of Wilms tumor, early onset and progressive renal failure and urogenital anomalies. Recent studies showed that exonic mutations at zinc finger domains of WT1 is responsible for pathogenesis of this syndrome. We analyzed WT1 mutations in 18 clinically diagnosed "Denys-Drash"(Drash) syndrome cases. 9 cases were typical Drash syndrome. Whereas another cases showed inronic point mutations at the splicing donor site at exon9. These mutations affect alternative splicing. The isoforms retaining three amino acids, KTS, are not produced. Clinical features of the patients with the intronic mutations correlated well with those of Frasier syndrome, characterized by more slowly progressing nephropathy than Denys-Drash syndrome, associated streak gonads and no development of Wilms' tumor. Our results indicate that WT1 isoforms with or without KTS have different functions in tumorigenesis and organogenesis of kidneys and gonads. Less
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