TWO C-MYC PROTEINS--ROLE IN CELL GROWTH & ONCOGENESIS

对c-myc的浓厚兴趣源于 C-myc表达与细胞增殖及预后的关系 从一个“激活的”myc与各种各样的 包括人类在内的不同物种的肿瘤。的总目标是 这一提议是为了确定微分合成是否 两种主要的c-myc蛋白(I和II)在控制 细胞增殖和肿瘤发生。两种c-myc蛋白 被发现通过N端延伸而彼此不同 由于在两个不同的地点被激发。较大的表格(c-myc I) 起始于外显子1中唯一的非ATG密码子 当细胞密度受到抑制时，细胞数量急剧增加。在……里面 此外，c-DNA的比例也发生了显著变化。 含有“激活的”c-myc基因的细胞中的myc I和Myc II。 C-myc I和II蛋白在增殖过程中的调节是 在法氏囊淋巴瘤细胞系中也发现了改变。这个 控制差示合成的因素和机理 将对这两种c-myc蛋白进行研究。比增长 刺激和抑制因素和条件将在 多种类型的细胞具有解离c-myc I和II的能力 综合。信使核糖核酸结构和启动因素的影响 在不同起始点上，将在正常情况下检查使用情况 细胞。在c-myc“激活”的淋巴瘤细胞中， C-基因的突变、前病毒整合位点和启动子的使用 将考察MYC的合成。最后，c-myc I的差异 和II功能将通过建立细胞系来检测 过度表达c-myc I或II。这将通过 起始密码子的定点突变。的能力 每个c-myc蛋白与ras共转化细胞，从而导致肿瘤。 和锚地独立性，增长因素要求，到 改变增长的研究应该确定是否有任何主要的 C-myc I和II的合成、调控和功能的差异 在增殖和肿瘤形成过程中通过已知的技术和 化验。

The considerable interest focused on c-myc stems from the correlation of c-myc expression with cellular proliferation and from the association of an "activated" myc with a wide variety of tumors in diverse species including human. The overall goal of this proposal is to determine if the differential synthesis of the two major c-myc proteins (I and II) has a role in the control of cellular proliferation and oncogenesis. The two c-myc proteins were found to differ from one another by an N-terminal extension due to initation at two distinct sites. The larger form (c-myc I) initiates at a unique non-ATG codon in exon 1 and was dramatically induced as cells became density-inhibited. In addition, there were significant changes found in the ratios of c- myc I and II in cells which contain an "activated" c-myc gene. The regulation of c-myc I and II protein during proliferation was also found to be altered in bursal lymphoma cell lines. The factors and mechanisms which control the differential synthesis of the two c-myc proteins will be studied. Specific growth stimulatory and inhibitory factors and conditions will be tested in a variety of cell types for their ability to dissociate c-myc I and II synthesis. The influence of mRNA structure and initiation factors on the differential initiation site usage will be examined in normal cells. In lymphoma cells with an "activated" c-myc, the effects of mutation, proviral integration site and promotor usage on c- myc synthesis will be examined. Finally, differences in c-myc I and II function will be examined by establishing cell lines which overexpress either c-myc I or II. This will be accomplished by site-directed mutagenesis of the initiation codons. The ability of each c-myc protein to cotransform cells with ras, to cause tumors and anchorage independence, to growth factor requirements, to alter growth studies should establish if there are any major differences in c-myc I and II synthesis, regulation and function during proliferation and oncogenesis by known techniques and assays.