p53 Proteins and Aflatoxin BI: The Good, the Bad, and the Ugly I f you want truly to understand something, try to change it.
-Kurt Lewin
The scientific community has learned and continues to learn much about the secrets of life and death at the cellular and molecular levels from study of the tumor suppressor gene p53. The above quote aptly reflects the saga of p53. Research on the p53 protein has proceeded at a breathtaking pace over the last few years. Basic research and clinical investigation have provided much needed insight into the structure and function of p53. Recently hailed as the "guardian of the genome," the p53 protein is the master switch of cellular growth, death, and malignant transformation. The p53 gene is the most frequently mutated gene in human cancers, and loss of wild-type function of the p53 protein is an important step in carcinogenesis.' Wild-type p53 exhibits both growth and transformation suppression activities, acting specifically at the G1 phase of the cell cy-~l e . ' , ~ Part of the tumor suppression function of p53 also stems from its role in inducing cell entry into apopto~is.~ Recent data on the normal functions of p53 suggest a potential role of p53 in differentiation of B cells and spermat~cytes.~ However, transgenic mice with germ-line deletion of the p53 gene show no developmental abnormalities, suggesting a limited role of p53 in normal cell growth and differentiation.6 These mice are prone to develop a variety of malignancies later in life, supporting the notion that p53, as a tumorsuppressor gene, is critical in controlling abnormal cell growth. It is interesting to note that the majority of tumors (lymphoma and gonadoblastoma) developed in these animals occurred in organs where p53 appears to function in differentiation. The precise mechanisms by which p53 performs these functions are largely unknown. Recently, several activities and cellular targets of p53 have been identified that could explain the functions of p53. p53 has been shown to exhibit sequencespecific DNA binding activity and activate cellular genes that are intimately involved in cell cycle regulation? Furthermore, cellular factors that have been Abbreviations: HCC, hepatocellular carcinoma; TGF-a, transforming