Figure 7.
Oncogenes and DNA damage activate p53 through distinct mechanisms. p19ARF acts as an intermediary in p53 activation by mitogenic oncogenes such as E1A and myc. In contrast, activation of p53 following DNA damage involves de novo phosphorylation of p53 on serine-15 (and other residues) by kinases such as the DNA-dependent protein kinase (DNA–PK) or the product of the ataxia-telangiectasia gene (ATM) (Shieh et al. 1997; Siliciano et al. 1997). Activation of p53 by oncogenes does not involve phosphorylation on serine-15, and both serine-15 phosphorylation (not shown) and p53 activation (Kamijo et al. 1997) following DNA damage are unimpaired in the absence of ARF. Therefore, the two upstream signaling pathways to p53 are fundamentally distinct.