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Comprehensive analysis of TRIM family ubiquitin ligases

TRIM家族泛素连接酶综合分析

基本信息

批准号：
18390079
负责人：
HATAKEYAMA Shigetsugu
金额：
$ 10.57万
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：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18390079/
关键词：
Ubiquitin Proteasome TRIM protein Cancer Ubiquitin ligase TRIMタンパク質

项目摘要

Ubiquitination is a versatile post-translational modification mechanism used by eukaryotic cells mainly to control protein levels through proteasome-mediated proteolysis. Ubiquitin conjugation is achieved by several enzymes that act in concert, a ubiquitin-protein ligase (E3). E3 is thought to be the component of the ubiquitin conjugation system that is most directly responsible for substrate recognition. Enzymes belonging to class E3 that have so far been identified include members of the HECT (homologous to E6-AP carboxyl terminus), RING-finger and U-box families of proteins. So far; we have published many articles about ubiquitination and oncogenesis.Tripartite motif (TRIM) proteins are characterized by the presence of a RING finger, one or two zinc-binding motifs named B-boxes and an associated coiled-coil region (BBRC357: 245, 2007; Mal Cell Biochem 307, 73, 2008; Mol Immunol 45 2045, 2008, Cancer Res, in press).We found that the putative E3 ubiquitin ligase TRIM68, which is prefe … More rentially expressed in prostate cancer cells, interacts with androgen receptor (AR) and enhances transcriptional activity of the AR in the presence of dihydrotestosterone (DHT). Overexpression of TRIM68 in prostate cancer cells caused an increase in secretion of prostate-specific antigen (PSA), one of the most reliable diagnostic markers for prostate cancer. Moreover, we showed that TRIM68 expression is significantly upregulated in human prostate cancers (Cancer Res, in press).Furthermore, we found by using yeast two-hybrid screening that TRIM32 binds to Abl-interactor 2 (Abi2), which is known as a tumor suppressor gene and a cell migration inhibitor Overexpression of TRIM32 promoted degradation of Abi2, resulting in enhancement of cell growth, transforming activity and cell motility In addition, we found that TRIM32 suppresses apoptosis induced by cis-diamminedichloroplatinum (II) (cDDP) in HEp2 cell lines. These findings suggest that TRIM32 is a novel oncogene that promotes tumor growth, metastasis and resistance to anti-cancer drugs. Less

泛素化是真核细胞主要通过蛋白酶体介导的蛋白质水解来控制蛋白质水平的一种通用的翻译后修饰机制。泛素结合是通过几种协同作用的酶实现的，即泛素-蛋白质连接酶（E3）。E3被认为是泛素缀合系统的组分，其最直接负责底物识别。迄今为止已经鉴定的属于E3类的酶包括HECT（与E6-AP羧基末端同源）、环指和U盒蛋白家族的成员。到目前为止; TRIM（Tripartite Motif）蛋白是一类具有RING指、一个或两个锌结合基序（B-boxes）和卷曲螺旋区的蛋白质（BBRC 357：245，2007; Mal Cell Biochem 307，73，2008; Mol Immunol 45 2045，2008，Cancer Res，出版中）。 ...更多信息在前列腺癌细胞中部分表达，与雄激素受体（AR）相互作用，并在双氢睾酮（DHT）存在下增强AR的转录活性。TRIM 68在前列腺癌细胞中的过表达导致前列腺特异性抗原（PSA）分泌增加，PSA是前列腺癌最可靠的诊断标志物之一。此外，我们发现TRIM 68表达在人前列腺癌中显著上调，此外，通过使用酵母双杂交筛选，我们发现TRIM 32与已知为肿瘤抑制基因和细胞迁移抑制剂的β-interactor 2（Abi 2）结合。TRIM 32的过表达促进Abi 2的降解，导致细胞生长的增强，转化活性和细胞运动性此外，我们发现TRIM 32抑制HEp 2细胞系中顺式二氨二氯铂（II）（cDDP）诱导的细胞凋亡。这些发现表明TRIM 32是一种新的癌基因，可促进肿瘤生长、转移和对抗癌药物的耐药性。少