Tumor suppressor p53 induction in response to cellular stresses activates the mitogen-activated protein kinase (MAPK) cascade through pathways involving Ras and RAF: p53's ability to activate this pathway is dependent on p53-mediated transcription. In order to investigate potential p53 target gene(s) involved, we utilized expression array analysis and identified heparin-binding epidermal growth factor-like growth factor (HB-EGF) as being markedly up-regulated by p53. In response to DNA damage, HB-EGF was induced in wild-type, but not in mutant p53-containing cells, implying its p53 dependence. HB-EGF neutralizing antibody and inhibitors of EGF receptor signaling abrogated p53-induced MAPK activation. Expression of HB-EGF was shown to protect cells from H(2)O(2)-induced apoptosis through MAPK activation. Additionally, the PI3K/Akt pathway was activated in response to p53 signaling through HB-EGF induction, and inhibition of MAPK and Akt activation after DNA damage decreased cell survival in wild-type p53-containing cells. All these findings point to a novel aspect of p53 function. Namely, p53-induced growth factors such as HB-EGF, which activate MAPK and Akt signaling, may be involved in a compensatory mechanism to alleviate adverse effects of cellular stresses.