Notch1 modulates oxidative stress induced cell death through suppression of apoptosis signal-regulating kinase 1

Abstract

Notch1 genes encode receptors for a signaling pathway that regulates various aspects of cell growth and differentiation; however, the roleofNotch1 signaling inp38 mitogen-activated protein kinase (MAPK) signaling pathway is still not well defined. In this study, we found that Notch1 intracellular domain (Notch1-IC) prevents oxida-tive stress-induced cell death through the suppression of the Apo-ptosis signal-regulating kinase (ASK)1 signaling pathway. Notch1-IC inhibited H2O2-induced activation of ASK1 and the activation of downstream kinases in the p38 MAPK signaling cascade. The results of both in vivo binding and kinase studies have revealed that ASK1 is the direct target of Notch1-IC, whereas it produced no effect on either MAP kinase kinase (MKK) 3 or p38 MAPK. Notch1-IC blocked both the homooligomerization of ASK1 and inhibited ASK1 activity. Furthermore, Notch1-IC facilitated the translocation of activated ASK1 toward the nucleus. Notch1 knockdown was determined to be highly susceptible to oxidative stress-induced activation of ASK1-MKK3/MKK6-p38 MAPK signaling cascade and cell death. Taken together, our findings suggest that Notch1-IC may act as a negative regulator in ASK1 signaling cascades.