Functional inactivation of p53 by gene mutation and deletion, protein degradation, or viral oncogene binding renders a mammalian cell susceptible to oncogenic stimuli and environmental insults that promote growth deregulation and malignant progression. Although a variety of mechanisms have been proposed for how p53 protects cells against neoplastic transformation, it is becoming clear that p53 integrates signals from the cell’s internal and external environment to respond to inappropriate growth promoting or growth inhibiting conditions (for review, see Gottleib and Oren 1995; Ko and Prives 1996; Levine 1997). This ‘‘sensor’’function of p53 makes it unusual in the tumor suppressor gene family. The list of stimuli that alter p53 activity is increasing and our understanding of the signal transduction pathways used to signal to p53 are starting to become elucidated.

The predominant regulation of p53 occurs at the protein level. Mutations in p53 that affect its conformation typically increase its half-life, in part by inhibiting degradation by the ubiquitin complex (Maki et al. 1996; Haupt et al. 1997; Kubbutat et al. 1997; Midgley and Lane 1997), and the majority of human tumor mutations decrease the sequence-specific DNA binding and transcriptional activity of p53 protein (Cho et al. 1994). In unstressed cells, p53 appears to be present at low levels and exists in a latent, inactive form that requires modification to become active. The types of modification that p53 is subjected to seem to be stress-, species-and celltype-specific. Levels and/or activity of p53 increase in response to DNA damaging agents (Maltzman and Czyzyk 1984; Kastan et al. 1991; Nelson and Kastan 1994), decreased oxygen (Graeber et al. 1994), oncogenic stimuli (Debbas and White 1993; Lowe and Ruley 1993; Hermeking and Eick 1994; Wanger et al. 1994; Serrano et al. 1997), cell adhesion (Nigro et al. 1997), altered ribonucleotide pools (Linke et al. 1996), and redox stress (Hainaut and Milner 1993a; Hupp et al. 1993). Although all of these stresses signal the activation of p53 protein, unique pathways appear to be utilized by the different stresses.