p53 induction of heparin-binding EGF-like growth factor counteracts p53 growth suppression through activation of MAPK and P13K/Akt signaling cascades

Tumor suppressor p53 induction in response to cellular stresses activates t he mitogen-activated protein kinase (MAPK) cascade through pathways involvi ng 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-bi nding 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 abro gated p53-induced MAPK activation. Expression of HB-EGF was shown to protec t cells from H2O2-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 d ecreased cell survival in wild-type p53-containing cells. All these finding s point to a novel aspect of p53 function. Namely, p53-induced growth facto rs such as HB-EGF, which activate MAPK and Akt signaling, may be involved i n a compensatory mechanism to alleviate adverse effects of cellular stresse s.