Function of MM-1, a novel c-Myc-binding protein, as a tumor suppressor

MM-1（一种新型 c-Myc 结合蛋白）作为肿瘤抑制因子的功能

• 批准号: 13672269
• 负责人: TAIRA Takahiro
• 金额: $ 2.62万
• 依托单位: HOKKAIDO UNIVERSITY
• 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-13672269/
• 关键词: c-Myc; MM-1; ubiquitin; tumor suppressor; proteasome; tumorgenesis; c-fms; protein degradation; 癌遺伝子; 発ガン; 転写因子; コリプレッサー; リンパ腫

1). Identification of a novel transrepression pathway of c-Myc and its target geneWe have found that MM-1 bound to TTFlβ, a transcriptional corepressor, and that MM-1 recruited a corepressor complex, including HDAC1 and mSin3, to c-Myc, thereby leading to repressing c-Myc transcription activity. To identify target genes to this pathway, a MycER cell line harboring a dominant-negative form of TIF1β, in which the corepressor complex was not recruited to c-Myc, was first established. DNA-microarray method was then applied to identify genes whose expressions were upregulated in this line compared to those in MycER cells. By this system we identified c-fms oncogene as the c-Myc-MM-1 repressed gene. It was then found that third E-box present in c-fms promoter was essential to be repressed by c-Myc.2). Identification of a novel degradation pathway of c-MycWe have also identified Elongin B, 26Sproteasome subunits Rpt3 and Rpn12 as MM-1-associated proteins. Since these proteins functions for ubiquitination and degradation of proteins, we then tested a possibility that MM-1 plays a role in c-Myc degradation. The results indicate that MM-1 stimulated c-Myc degradation through the novel E3 ubiquitin ligase complex, including Spk2, Cullin 1,Elongon BThese findings indicate that MM-1 is a key protein that negatively regulates c-Myc function and that lost of these functions of MM-1 by mutations leads to tumor formation by c-Myc

1）。我们发现MM-1与转录辅阻遏物TTF 1 β结合，并且MM-1向c-Myc募集辅阻遏物复合物，包括HDAC 1和mSin 3，从而导致抑制c-Myc的转录活性。为了鉴定该途径的靶基因，首先建立了一种携带显性阴性形式的TIF 1 β的MycER细胞系，其中辅阻遏物复合物不被募集到c-Myc。然后应用DNA微阵列方法来鉴定在该细胞系中与MycER细胞中相比表达上调的基因。通过该系统我们鉴定出c-fms癌基因为c-Myc-MM-1抑制基因。然后发现c-fms启动子中存在的第三个E-box是c-Myc抑制所必需的。c-Myc新降解途径的鉴定我们还鉴定了延伸蛋白B、26 S蛋白酶体亚基Rpt 3和Rpn 12作为MM-1相关蛋白。由于这些蛋白质的功能是蛋白质的泛素化和降解，因此我们测试了MM-1在c-Myc降解中发挥作用的可能性。结果表明，MM-1通过新的E3泛素连接酶复合物（包括Spk 2、Cullin 1、Elongon B）刺激c-Myc降解。这些发现表明，MM-1是负调节c-Myc功能的关键蛋白，MM-1的这些功能的缺失导致c-Myc形成肿瘤。

项目成果

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