The complexity of p53 modulation: emerging patterns from divergent signals.

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-, speciesand 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. Is p53 protein accumulation needed for p53 activation or are modifications necessary for p53 activation separable from the modifications required for p53 protein accumulation? Both the modifiers and the types of modification will be important to sort out to understand the relationship between accumulation and activation. Although the two appear to be separable (Chernov et al. 1998; Hupp et al. 1995), it is possible that both are essential for full tumor suppressor function. The importance of p53 and modifications that affect its functions are not limited to malignant disease. The activity of p53 can increase in normal tissues when undergoing pathophysiological changes that result in oxidative or redox stress, such as ischemia and reperfusion injury of the brain, heart, and other tissues. Thus both oxidative stress generated by hydrogen peroxide, as well as reducing stresses generated by the lack of oxygen, appear to be potent stimulators of p53 activity. In addition, the link between p53 function and the modulation of angiogenesis further implicates p53 pathways in the processes of wound healing (Antoniades et al. 1994) and ischemic injury responses (Banasiak and Haddad 1998). At present little is known about the pathways that control p53 activity in response to ischemia and reperfusion in normal tissues, and this area should be fertile ground for research in future years. In this review, we discuss what is known about how various stressors signal to p53 and the various mechanisms utilized to modulate p53 activity. Because of the focus on signaling to p53, we will not attempt to discuss the ‘‘downstream’’ physiologic effects of p53 activation such as cell-cycle perturbations or cell death.