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

我们已经鉴定了几种c-Myc结合蛋白，它们的功能可以改变或调节c-Myc的多种功能。我们鉴定的蛋白质是AMY-1、MM-1、MSSP、CBF/NF-Y、ORC1、CDC6和CDK抑制因子p21。AMY-1、MM-1和MSSP是新发现的蛋白质，并克隆了它们的cDNAs。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、ORC1和CDC6)和细胞周期运动因子(P21)。在c-Myc转录功能方面，AMY-1为正性转录因子，其余为负性转录因子。尤其是MM-1具有潜在的肿瘤抑制作用，MM-1第157位氨基酸从丙氨酸到精氨酸的取代在淋巴瘤、白血病和喉癌的培养细胞和癌组织中都是相当常见的。这一精氨酸突变消除了MM-1对c-Myc的负面影响。除了AMY-1的c-Myc相关功能外，AMY-1还包含影响A-K和肌动蛋白聚合的动态功能。AMY-1与AKAP84及其选择性剪接变异体AKAP149结合，两者都将A-激酶锚定在相应的细胞位置。AMY-1与AKAP84结合后，A-激酶复合体在精子线粒体表面发生运动，起到精子动员的作用。AMY-1与AKAP149结合可使肌动蛋白在细胞核周围的线粒体上聚合。这些肌动蛋白细丝在结构上的不同组织可能倾向于肿瘤的形成。MSSP的零突变在发育阶段往往是致命的。这些发现表明，除了对c-Myc功能的调节外，c-Myc结合蛋白还在细胞成熟、受精的关键步骤中发挥作用。

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.