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.
