Carcinogenesis Advance Access originally published online on November 4, 2006
Carcinogenesis 2007 28(4):777-784; doi:10.1093/carcin/bgl211
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Tumor prone phenotype of mice deficient in a novel apoptosis-inducing gene, drs
1 Department of Microbiology, Shiga University of Medical Science Setatsukinowa-cho, Otsu, Shiga 520-2192, Japan
2 Department of Pathology, Shiga University of Medical Science Setatsukinowa-cho, Otsu, Shiga 520-2192, Japan
3 Clinical Laboratory Medicine, Shiga University of Medical Science Setatsukinowa-cho, Otsu, Shiga 520-2192, Japan
4 Central Research Laboratory, Shiga University of Medical Science Setatsukinowa-cho, Otsu, Shiga 520-2192, Japan
5 Department of Infectious Diseases, Osaka Prefectural Institute of Public Health Nakamichi, Higashinari-ku, Osaka, Osaka 537-0025, Japan
6 Department of Global Epidemiology, Research Center for Zoonosis Control, Hokkaido University N18, W9, Kita-ku, Sapporo, Hokkaido 060-0818, Japan
7 Division of Diagnostic Pathology, Shiga University of Medical Science Setatsukinowa-cho, Otsu, Shiga 520-2192, Japan
8 SPOC Inc, Reading Venture Plaza 5F 75-1, Ono-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0046, Japan
9 Animal Research Laboratory, Bioscience Education-Research Center, Akita University 1-1-1 Hondo, Akita, Akita 010-8543, Japan
10 Division of Mammalian Development, National Institute of Genetics Yata 1111, Mishima, Shizuoka 411-8540, Japan
11Present address: Moores UCSD Cancer Center, University of California San Diego, School of Medicine 3855 Health Sciences Drive, La Jolla, CA 92093-0820, USA
12Present address: Chiba Cancer Center Research Institute 666-2 Nitona, Chuoh-ku, Chiba 260-717, Japan
*To whom correspondence should be addressed. Tel: +81 77 548 2177; Fax: +81 77 548 2404; Email: hirokazu{at}belle.shiga-med.ac.jp
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 (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.
Abbreviations: KO, knockout; ER, endoplasmic reticulum.
These authors contributed equally to this work. Received August 24, 2006; revised October 21, 2006; accepted October 24, 2006.
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