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

对c-myc的极大兴趣源于 c-myc表达与细胞增殖的相关性 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 这个建议是为了确定是否差分合成的 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 被发现彼此不同的N-末端延伸 是因为两个不同的部位都有感染 c-myc I（c-myc I） 起始于外显子1中的独特非ATG密码子， 随着细胞密度受到抑制， 在 此外，还发现c- myc I和myc II在含有“激活的”c-myc基因的细胞中。 c-myc I和c-myc II蛋白在细胞增殖过程中的调节作用， 也发现在囊淋巴瘤细胞系中改变。 的 控制差异合成的因素和机制 将研究两种c-myc蛋白的差异。 比生长 刺激和抑制因子和条件将在 多种细胞类型，因为它们能够解离c-myc I和II 合成. mRNA结构和起始因子的影响 将在正常情况下检查不同起始位点的使用情况 细胞 在c-myc“激活”的淋巴瘤细胞中， 的突变，前病毒整合位点和启动子使用的c- 将检测myc的合成。 最后，c-myc I 和II的功能将通过建立细胞系来检查， 过表达c-myc I或II。 这将通过 起始密码子的定点诱变。 的能力 每个c-myc蛋白与ras共同转化细胞， 和锚定独立性，生长因子的要求， 生长研究应确定是否存在任何主要的 c-myc I和II合成、调节和功能的差异 在增殖和肿瘤发生过程中， 测定。

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.