P53-GUANINE NUCLEOTIDE REGULATOR

最近的研究清楚地表明，p53基因的改变， 抑癌基因是肿瘤发生过程中重要的分子事件。 以来 Baker等人（1989）关于结肠癌的开创性研究， 在不同的人类癌症中p53基因改变的大量文献。 尽管这种新的知识的优势明显， 人类癌症中p53突变的频率，新诊断，预后 并且基于p53的这种特征的治疗方法还没有出现。 造成这种情况的一个关键原因是，在整个数据收集过程中， 在人类肿瘤中p53的改变，p53的细胞功能仍然存在， 未知 然而，最近，一种生物化学功能被定义为 哺乳动物细胞中的p53（Sherley，1991;见附录）。 抑癌基因 调节肌苷-5 '-单磷酸脱氢酶的表达 （IMPDH），鸟嘌呤核苷酸生物合成的限速酶。 这一发现暗示鸟嘌呤核苷酸代谢是一个关键的细胞 肿瘤进展过程。 鸟嘌呤核苷酸如GTP和cGMP是 关键的细胞调节核苷酸。 在其监管角色中， 是信号转导中信号放大的关键物种 激活细胞生长的途径。 因此，鸟嘌呤的生物合成 核苷酸是调节细胞增殖的潜在控制点， 增长p53突变代表了一种方式， 可能被破坏，从而导致肿瘤发生。 的 生物化学和分子表征，这种新定义的 p53-鸟嘌呤核苷酸调控系统无疑会导致 发现新的细胞成分具有类似的作用， 致癌作用 通过这种方式，p53可以提供与新基因的联系， 与人类肿瘤的形成有关 的识别 每一个新的癌症基因都有可能发现一种新的 对抗癌症的策略。

Recent studies have clearly demonstrated that alterations in the p53 antioncogene are important molecular events in carcinogenesis. Since the seminal studies of Baker et al. (1989) on colon carcinoma, there has grown a vast literature on p53 gene alterations in diverse human cancers. Despite the apparent advantage of this new knowledge of the high frequency of p53 mutations in human cancers, new diagnostic, prognostic and therapeutic approaches based on this feature of p53 have not emerged. A key reason for this situation is that throughout the collection of data on p53 alterations in human tumors, the cellular function of p53 remained unknown. Recently, however, a biochemical function has been defined for p53 in mammalian cells (Sherley, 1991; see Appendix). The antioncogene regulates the expression of inosine-5'-monophosphate dehydrogenase (IMPDH), the rate limiting enzyme for guanine nucleotide biosynthesis. This finding implicates guanine nucleotide metabolism as a key cellular process in tumor progression. Guanine nucleotides like GTP and cGMP are key cellular regulatory nucleotides. Among their regulatory roles, they are critical species for signal amplification in signal transduction pathways that activate cells to grow. Thus, the biosynthesis of guanine nucleotides is a potential control point for the regulation of cell growth. p53 mutations represent one way by which this cellular process may be disrupted and, thereby, contribute to tumorigenesis. The biochemical and molecular characterization of this newly defined p53-guanine nucleotide regulatory system will undoubtedly lead to the discovery of new cellular components with similar roles in carcinogenesis. In this way, p53 may provide a link to new genes which are involved in the formation of human tumors. The identification of each new cancer gene brings the potential for the discovery of a new strategy to combat cancer.