Carcinogenesis Advance Access published online on November 4, 2006
Carcinogenesis, doi:10.1093/carcin/bgl211
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1 Department of Microbiology, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, Shiga 520-2192, Japan
* To whom correspondence should be addressed. 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-xS, 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 mouse. Between 7-12 months after birth, malignant tumors including lymphomas, lung adenocarcinomas, and hepatomas were generated in about 30% of the drs knockout (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.
Received August 24, 2006
Revised October 21, 2006
Accepted October 24, 2006
CANCER BIOLOGY
Tumor prone phenotype of mice deficient in a novel apoptosis-inducing gene, drs
Yukihiro Tambe 1 12, Atsuko Yoshioka-Yamashita 2 12, Ken-ichi Mukaisho 3, Seiki Haraguchi 4, Tokuhiro Chano 5, Takahiro Isono 6, Takao Kawai 7, Yasuhiko Suzuki 8, Ryoji Kushima 9, Takanori Hattori 3, Motohito Goto 10, Shuichi Yamada 11, Makoto Kiso 12, Yumiko Saga 12, and Hirokazu Inoue 1 *
2 Department of Microbiology, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, Shiga 520-2192, Japan; Present Address: Moores UCSD Cancer Center, University of California San Diego, School of Medicine, 3855 Health Sciences Drive, La Jolla, CA 92093-0820, USA
3 Department of Pathology, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, Shiga 520-2192, Japan
4 Department of Microbiology, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, Shiga 520-2192, Japan; Present Address: Chiba Cancer Center Research Institute, 666-2 Nitona, Chuoh-ku, Chiba 260-717, Japan
5 Clinical Laboratory Medicine, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, Shiga 520-2192, Japan
6 Central Research Laboratory, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, Shiga 520-2192, Japan
7 Department of Infectious Diseases, Osaka Prefectural Institute of Public Health, Nakamichi, Higashinari-ku, Osaka, Osaka 537-0025, Japan
8 Department of Global Epidemiology, Research Center for Zoonosis Control, Hokkaido University, N18, W9, Kita-ku, Sapporo, Hokkaido 060-0818, Japan
9 Division of Diagnostic Pathology, Shiga University of Medical Science, Setatsukinowa-cho, Otsu, Shiga 520-2192, Japan
10 SPOC Inc, Reading Venture Plaza 5F, 75-1, Ono-cho, Turumi-ku, Yokohama, Kanagawa 230-0046, Japan
11 Animal Research Laboratory, Bioscience Education-Research Center, Akita University, 1-1-1 Hondo, Akita, Akita 010-8543, Japan
12 Division of Mammalian Development, National Institute of Genetics, Yata 1111, Mishima, Shizuoka 411-8540, Japan
Hirokazu Inoue, E-mail: hirokazu{at}belle.shiga-med.ac.jp
Abstract
12These authors contributed equally to this work
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