p53 tumor suppressor gene: from the basic research laboratory to the clinic--an abridged historical perspective.

Tumor suppressor genes maintain tissue homeostasis by controlling cellular proliferation, terminal differentiation and programmed cell death (1,2). The p53 tumor suppressor gene has come to the forefront of cancer research because it is commonly mutated in human cancer and the spectrum of p53 mutations in these cancers is providing clues to the etiology and molecular pathogenesis of cancer (3-8). Of the ~6.5 million cancer cases worldwide each year, 2.4 million tumors are estimated to contain a p53 mutation (examples shown in Figure 1). In the most common lethal types of cancers found in the US population, the estimate is over 300 000 cancers (Table I). These are necessarily crude estimates, because the mutation frequency differs among populations due to dissimilar exposures to environmental carcinogens (and perhaps other reasons such as genetic variation among ethnic groups of genes involved in critical biologic pathways), and selection bias might confound figures derived from early studies. Nevertheless, the high frequency of p53 mutations attests to their potential importance in the pathogenesis, diagnosis and treatment of human cancer. The 16 year history of p53 investigations is a paradigm in cancer research, illustrating the convergence of previously parallel lines of basic, clinical, and epidemiologic investigation and the rapid transfer of research findings from the laboratory to the clinic. This rich history of scientific accomplishment is briefly reviewed in Table n. The initial observations in 1979 of a cellular protein of ~53 kDa complexing with the large T antigen of SV-40 DNA virus, and of accumulation of p53 protein in the nuclei of neoplastic rodent cells stimulated several researchers to investigate the presence of p53 in tumors and its potential role in carcinogenesis. The p53 gene cloned from neoplastic rodent and human cells was then shown to have weak oncogenic activity. In the late 1980s, researchers discovered that they were studying p53 mutants instead of the wild-type gene; thus the first decade of p53 history can be confusing to the novice reader. Whereas many p53 mutants acted as a dominant-acting oncogene, the wild-type gene suppressed both the neoplastic transformation of rodent fibroblasts in vivo and the growth of rodent and human cancer cells in vitro and in vivo. To the surprise of cancer researchers in 1989, p53 was found to be mutated frequently in human cancers, and the search for p53 functions intensified which has resulted in an explosion of reports in the literature (Figure 2). Recent studies indicate that the p53 protein is involved in gene transcription, DNA synthesis and repair, senescence, genomic plasticity, and in programmed cell death (2-5,7,913). These complex biochemical processes are performed by multicomponent protein machines, so it is not surprising that the p53 protein forms complexes with other cellular proteins, and that oncoviral proteins of certain DNA viruses alter the functions of these protein machines by binding to p53 and perturbing its interaction with other cellular protein components (Figure 3). Ongoing studies are both defining the threedimensional structure of these p53-containing protein complexes and uncovering the regulation of their precise functions. p53 is clearly a component in a biochemical pathway(s) (5) central to human carcinogenesis; p53 protein alterations due to missense mutations and loss of p53 protein by nonsense or frameshift mutations provide a selective advantage for clonal