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Regulation of cell-cycle movement and cell transformation by nuclear oncogenes.

核癌基因对细胞周期运动和细胞转化的调节。

基本信息

批准号：
10470477
负责人：
ARIGA Hiroyoshi
金额：
$ 6.66万
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：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10470477/
关键词：
c-myc PRC1 tumor suppresser transcrition cell cycle apoptosis phosphorylation chromatin Pim-1

项目摘要

We have identified several c-Myc binding proteins whose functions would modify or regulate the versatile functions of c-Myc. Proteins we identified are AMY-1, MM-1, MSSP, CBF/NF-Y, ORC1, CDC6 and cdk inhibitor p21. AMY-1, MM-1 and MSSP are novel proteins and their cDNAS were cloned. These proteins were classified to the categories including factors for transcription (AMY-1, MM-1 and CBF/NF-Y), DNA replication (MSSP, ORC1 and CDC6) and cell-cycle movement (p21). In terms of transcription function of c-Myc, AMY-1 acted as a positive factor and the others were as negative factors. Especially MM-1 has a character for a putative tumor suppresser; the substitution of amino acid from alanine to arginine at a position of 157 of MM-1 was quite frequently occurred in cells derived from both cultured cells and cancer patient tissues of lymphoma, leukemia and tong cancer. This arginine mutation abrogated the negative effects of MM-1 on c-Myc.In addition to c-Myc-related function of AMY-1, AMY-1 was found to contain the dynamic function affecting A-kinase and actin polymerization. AMY-1 bound to AKAP84 and its alternative splicing variant, AKAP149, both of which anchored A-kinase to the respective cell location. After AMY-1 bound to AKAP84, A-kinase complex turned to move on the surface of mitochondria of sperm and worked for sperm mobilization. AMY-1 bound to AKAP149 made the actin be polymerized on the mitochondria around nucle. These structural different organization of actin filaments may tend to the tumor formation.Null-mutation of MSSP tended to be lethal during developmental stage. These finding altogether suggest that c-Myc binding proteins play roles at crucial steps of cell maturation, fertilization in addition to the modulation to c-Myc functions.

我们已经鉴定了几种c-Myc结合蛋白，其功能将修饰或调节c-Myc的多功能。我们鉴定的蛋白质是AMY-1、MM-1、MSSP、CBF/NF-Y、ORC 1、CDC 6和cdk抑制剂p21。AMY-1、MM-1和MSSP是新发现的蛋白质，已克隆了它们的cDNA。这些蛋白质分为转录因子（AMY-1、MM-1和CBF/NF-Y）、DNA复制因子（MSSP、ORC 1和CDC 6）和细胞周期运动因子（p21）。就c-Myc的转录功能而言，AMY-1为阳性因子，其余为阴性因子。特别是MM-1具有推定的肿瘤抑制剂的特征; MM-1的157位氨基酸从丙氨酸到精氨酸的取代非常频繁地发生在来源于淋巴瘤、白血病和肺癌的培养细胞和癌症患者组织的细胞中。AMY-1除了具有与c-Myc相关的功能外，还具有影响A激酶和肌动蛋白聚合的动态功能。AMY-1与AKAP 84及其可变剪接变体AKAP 149结合，这两者都将A激酶锚定在各自的细胞位置。AMY-1与AKAP 84结合后，A-激酶复合物在精子线粒体表面移动，起到精子动员的作用。AMY-1与AKAP 149结合，使肌动蛋白在核周围的线粒体上聚合。这些结构上的差异可能导致肿瘤的形成，MSSP的缺失突变在发育阶段具有致死性。这些发现共同表明，c-Myc结合蛋白除了对c-Myc功能的调节外，还在细胞成熟、受精的关键步骤中发挥作用。