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Functions of Myc and c-Myc-binding proteins

Myc 和 c-Myc 结合蛋白的功能

基本信息

批准号：
14370736
负责人：
ARIGA Hiroyoshi
金额：
$ 8.83万
依托单位：
HOKKAIDO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370736/
关键词：
c-Myc MM-1 AMY-1 tumor suppressor BIG2 protein degradatin Golgi apparatu ubiquitin AKAP 精子形成 c-fms PKA

项目摘要

1).Identification of a novel transrepression pathway of c-Myc and its target geneWe have found that MM-1 bound to TIF13, 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 TIFiβ, 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 m c-fins promoter was essential to be repressed by c-Myc.2). Identification of a novel degradation pathway of c-Myc.We have also identified Elongin B, 26Sproteasome subunits Rpt3 and Rpn12 as MM-1-associated proteins. Since these proteins functions for ub … More iquitination 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.3) AMY-1 was found to bind to the protein kinase A (P1(A) regulatory subunit type 2 (RII)-binding domains of several PKA-anchoring proteins, AKAPs, including AKAP149, S-AKAP84 and AKAP95, and to be localized in the cytoplasm or nuclei depending on associated AKAPs AMY-1 was also localized in the Golgi apparatus. AMY-1 bound to the first RII-binding domains of the brefeldin A-inhibited guanine nucleotide-exchange proteins BIG2 and BIG1 and colocalized with BIG2 even in the presence of brefeldin A, which inhibits guanine nucleotide-exchange activity of BIG2. AMY-1 was also found to be localized in the trans-Golgi apparatus. These results suggest that AMY-1 as a cofactor plays a role in guanine nucleotide-exchange reaction of BIG2 or BIG1. Less

1).c-Myc及其靶基因的新型反式阻抑途径的鉴定我们发现MM-1与转录辅阻遏物TIF13结合，并且MM-1将包括HDAC1和mSin3的辅阻遏物复合物招募到c-Myc，从而抑制c-Myc转录活性。为了识别该途径的靶基因，首先建立了含有 TIFiβ 显性失活形式的 MycER 细胞系，其中辅阻遏物复合物未被招募到 c-Myc。然后应用 DNA 微阵列方法来鉴定与 MycER 细胞中的基因相比，该细胞系中表达上调的基因。通过该系统，我们将 c-fms 癌基因鉴定为 c-Myc-MM-1 抑制基因。然后发现存在的第三个E-box m c-fins 启动子对于被c-Myc 抑制至关重要。2)。鉴定了 c-Myc 的新降解途径。我们还鉴定了 Elongin B、26Sproteasome 亚基 Rpt3 和 Rpn12 作为 MM-1 相关蛋白。由于这些蛋白质的功能是蛋白质的 ub … More 停止和降解，因此我们随后测试了 MM-1 在 c-Myc 降解中发挥作用的可能性。结果表明，MM-1 通过新型 E3 泛素连接酶复合物（包括 Spk2、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，突变导致 MM-1 的这些功能丧失，导致 c-Myc 形成肿瘤。3) AMY-1 被发现与蛋白激酶 A 结合 (P1(A) 调节亚基 2 型 (RII) 结合域是多种 PKA 锚定蛋白、AKAP（包括 AKAP149、S-AKAP84 和 AKAP95）的结合域，并且根据相关 AKAP 定位在细胞质或细胞核中。AMY-1 也定位在高尔基体中。AMY-1 与第一个 RII 结合域结合布雷菲德菌素 A 抑制鸟嘌呤核苷酸交换蛋白 BIG2 和 BIG1，并且即使在布雷菲德菌素 A 存在的情况下也与 BIG2 共定位，布雷菲德菌素 A 抑制 BIG2 的鸟嘌呤核苷酸交换活性。 AMY-1 还被发现位于跨高尔基体中。这些结果表明 AMY-1 作为辅助因子在鸟嘌呤核苷酸交换反应中发挥作用 BIG2 或 BIG1。少