title: Tumor prone phenotype of mice deficient in a novel apoptosis-inducing gene, drs.
abstract: The drs gene was originally isolated as a suppressor of v-src transformation. Expression of drs mRNA is markedly downregulated in a variety of human cancer cell lines and tissues, suggesting the potential role of this gene as a tumor suppressor. Previously, we found that Drs protein associates with ASY/Nogo-B/RTN-x(S), an apoptosis-inducing protein in the endoplasmic reticulum, and sequentially activates caspases to induce apoptosis in human cancer cells without involvement of the mitochondria. In this study, we investigated the tumor suppressor function of drs and the correlation between Drs-mediated apoptosis and tumor suppression by generating a gene-knockout (KO) mouse. Between 7 and 12 months after birth, malignant tumors including lymphomas, lung adenocarcinomas and hepatomas were generated in about 30% of the drs KO mice, whereas no tumors were found in any of the wild-type mice during the same period of time. drs KO embryonic fibroblasts also showed enhanced sensitivity to transformation by v-src oncogene. Reintroduction of drs into a tumor cell line derived from the tumor of a drs KO mouse led to the suppression of tumor formation in nude mice, which was accompanied by enhanced apoptosis and the activation of caspase-9 and -3. Furthermore, introduction of drs into this cell line enhanced sensitivity to apoptosis mediated by caspase-3, -9 and -12 under low serum culture conditions. The present results thus indicate that drs contributes to the suppression of malignant tumor formation, and this suppression is closely correlated with drs-mediated apoptosis.
authors.affiliation: Department of Microbiology, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, Shiga 520-2192, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Tambe
authors.forename: Atsuko
authors.initials: A
authors.lastname: Yoshioka-Yamashita
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Mukaisho
authors.forename: Seiki
authors.initials: S
authors.lastname: Haraguchi
authors.forename: Tokuhiro
authors.initials: T
authors.lastname: Chano
authors.forename: Takahiro
authors.initials: T
authors.lastname: Isono
authors.forename: Takao
authors.initials: T
authors.lastname: Kawai
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Ryoji
authors.initials: R
authors.lastname: Kushima
authors.forename: Takanori
authors.initials: T
authors.lastname: Hattori
authors.forename: Motohito
authors.initials: M
authors.lastname: Goto
authors.forename: Shuichi
authors.initials: S
authors.lastname: Yamada
authors.forename: Makoto
authors.initials: M
authors.lastname: Kiso
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Saga
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Inoue
mesh_terms: D000230:Adenocarcinoma / Q000209:etiology / Q000473:pathology*; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D020868:Gene Silencing / Q000502:physiology*; D016147:Genes, Tumor Suppressor; D006801:Humans; D007124:Immunoenzyme Techniques; D007668:Kidney / Q000378:metabolism; D008175:Lung Neoplasms / Q000209:etiology / Q000473:pathology*; D008223:Lymphoma / Q000209:etiology / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011995:Recombination, Genetic; D014162:Transfection
chemical_list: D008565:Membrane Proteins; D012333:RNA, Messenger; C486298:Srpx protein, mouse; D020169:Caspases