Studies on molecular mechanism of tumor suppression by the drs gene

drs基因抑制肿瘤的分子机制研究

• 批准号: 13670211
• 负责人: INOUE Hirokazu
• 金额: $ 2.3万
• 依托单位: Shiga University of Medical Science
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670211/
• 关键词: Tumor suppressor gene; Drs gene; Apoptosis; Knockout mouse; がん抑制遺伝子; drs遺伝子

The drs gene was originally isolated as a suppressor gene against v-src transformation. We have shown that expression of drs mRNA was markedly reduced in a variety of human cancer cell lines, and introduction of drs cDNA by retrovirus vector into these cancer cell lines caused suppression of anchorage-independent growth. These findings indicate that downregulation of drs mRNA is closely correlated with expression of malignant phenotype in development of human cancers and the drs gene act as a tumor suppressor. In this project, we performed the research to clarify the mechanism of tumor suppression by the drs gene and obtained the following results.1. Identification of Drs-binding proteinsWe have established the systems to identify Drs-binding proteins by immunoprecipitation and peptide mass fingerprinting methods in cells expressing high level of Drs protein. By using these systems, we found that several cellular proteins including GRF78/BiP and α-glucosidase-α subunit are associated w … More ith Drs.2. Construction and analysis of drs-knockout mouseBy gene-targetting techniques, we succceeded in making germ line-transmitted drs kockout mouse. Analyses of Drs KO mouse on tumor formation and physiological function of the drs gene are in progress.3. Investigation of correlation between expression of malignant phenotypes and downregulation of drs gene in human cancersTo clarify the role of the drs gene in the development of human cancers, we examined the expression of the drs mRNA and the status of genome DMA of drs in normal, benign, and malignant tissues of colon, lung, prostate cancers and lymphomas of ATL We found that drs mRNA was downregulated in malignant tissues of these cancers. Neither gross deletion nor rearrangement of the drs genome was detected in these malignant tissues.4. Apotosis-inducing activity of drs.Wefound that drs can induce apoptosis by activation of caspase-12, -9-, -3 in human cancer cell lines, suggesting a novel apoptosis-mediated pathway of tumor suppression by the drs gene. Less

drs基因最初是作为v-src转化的抑制基因分离的。我们已经表明，在各种人类癌细胞系中，drs mRNA的表达显著降低，并且通过逆转录病毒载体将drs cDNA引入这些癌细胞系中引起对锚定非依赖性生长的抑制。这些结果表明，在人类癌症的发展过程中，drs mRNA的下调与恶性表型的表达密切相关，并且drs基因起着抑癌作用。本课题对drs基因的抑瘤机制进行了研究，取得了以下成果：1. Drs结合蛋白的鉴定我们在高表达Drs蛋白的细胞中建立了免疫沉淀法和肽质量指纹法鉴定Drs结合蛋白的系统。通过使用这些系统，我们发现包括GRF 78/BiP和α-葡萄糖苷酶-α亚基在内的几种细胞蛋白质与蛋白质的表达相关。 ...更多信息 博士2 drs基因敲除小鼠的构建与分析利用基因打靶技术，我们成功地建立了生殖系传递的drs基因敲除小鼠。Drs基因敲除小鼠的肿瘤形成和drs基因生理功能的研究正在进行中.为了阐明drs基因在人类癌症发展中的作用，我们检测了在正常、良性和恶性结肠、肺、结肠和结肠癌组织中drs mRNA的表达和drs基因组DNA的状态。我们发现在这些癌症的恶性组织中drs mRNA下调。在这些恶性肿瘤组织中未检测到drs基因组的缺失和重排。drs的诱导凋亡活性研究发现，drs可以通过激活caspase-12，-9-，-3诱导人癌细胞凋亡，提示drs基因可能是一种新的肿瘤抑制途径。少

项目成果

T.Kuwai et al.: "Isolation of a novel mouse variant of the drs tumor suppressor gene"Cancer Letters. 183. 79-86 (2002)

T.Kuwai 等人：“drs 肿瘤抑制基因的新型小鼠变体的分离”《癌症快报》。

Q.Li et al.: "Link of a new type of apoptosis -inducing gene ASY/Nogo-B to human cancer"Oncogene. 20. 3929-3936 (2001)

Q.Li等人：“新型凋亡诱导基因ASY/Nogo-B与人类癌症的联系”癌基因。

Mukaisho,K., Suo,M., Shimakage,M., Kushima,R., Inoue,H., and Hattori,T.: "Down-regulation of drs mRNA in colorectal neoplasms"Jap.J.Cancer Res.. 93. 888-893 (2002)

Mukaisho,K.、Suo,M.、Shimakage,M.、Kushima,R.、Inoue,H. 和 Hattori,T.：“结直肠肿瘤中 drs mRNA 的下调”Jap.J.Cancer Res..

T.Kawai et al.: "Isolation of a novel mouse variant of the drs tumor suppressor gene"Canner Letters. 183. 79-86 (2002)

T.Kawai 等人：“drs 肿瘤抑制基因的新型小鼠变体的分离”Canner Letters。

N.Yoshioka et al.: "Suppression of anchorage-independent growth of human cancer cell lines by the TRIF52/periostin/OSF-2 gene"Exp. Cell. Res.. 279. 91-99 (2002)

N.Yoshioka 等人：“TRIF52/periostin/OSF-2 基因抑制人类癌细胞系的锚定非依赖性生长”Exp。