权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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).我们发现MM-1与转录辅阻遏物TIF 13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TIFiβ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。然后发现第三个E-box存在的mc-fins启动子对于被c-Myc抑制是必需的。我们还鉴定了MM-1相关蛋白Elongin B、26 S蛋白酶体亚基Rpt 3和Rpn 12。由于这些蛋白质的功能为ub ...更多信息通过测定蛋白质的定量和降解，我们测试了MM-1在c-Myc降解中起作用的可能性。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，这些发现表明MM-1是负调节c-Myc功能的关键蛋白，并且MM-1的这些功能的缺失通过突变导致c-Myc的肿瘤形成。几种PKA锚定蛋白AKAP（包括AKAP 149、S-AKAP 84和AKAP 95）的2型调节亚基（RII）结合结构域，并取决于相关AKAP而定位于细胞质或细胞核中，AMY-1也定位于高尔基体中。AMY-1结合到布雷菲德菌素A抑制的鸟嘌呤核苷酸交换蛋白BIG 2和BIG 1的第一RII结合结构域，并且即使在布雷菲德菌素A存在下也与BIG 2共定位，这抑制了BIG 2的鸟嘌呤核苷酸交换活性。AMY-1也被发现定位在trans-Golgi器。这些结果表明，AMY-1作为辅助因子在BIG 2或BIG 1的鸟嘌呤核苷酸交换反应中起作用。少