Mechanism of NF-κB Activation Induced by γ-irradiation in B Lymphoma Cells : Role of Ras

Abstract

Nuclear factor (NF)-κB is a ubiquitous transcription factor involved in diverse cellular responses to various stimuli, including growth factors and radiation stress. Recently it was reported that γ‐irradiation (γ-IR) upregulates allergy-associated adhesion molecule CD23 on B cells and monocytes via NF-κB activation. In the present study, the mechanism of NF-κB activation by γ-IR was investigated to understand the signaling pathways involved in IR-induced, NF-κB-mediated enhancement of CD23 expression. In human B-cell line Ramos, γ-IR induced a dose-dependent increase of nuclear translocation and transcriptional activity of NF-κB. The γ-IR-induced NF-κB activation in these cells was sensitive to a proteosome inhibitor MG132 and an antioxidant, pyrollidine dithiocarbamate (PDTC), which suggests that γ-IR-induced NF-κB activation proceeds via IκB gradation and redox regulation. Since Ras was shown to play a role in NF-κB-mediated survival and inflammation of cancer cells against radiation, the role of Ras signaling in the γ-IR-induced NF-κB activation in these transformed B cells was examined. Transfection and overexpression of dominant active Ras produced an increase in NF-κB activity as shown by DNA binding and transcriptional activities of the κB-dependent reporter gene. γ-IR, however, did not induce Erk activation, nor the γ-IR-induced κB activity that was suppressed by inhibitors of Ras/Raf interaction or MEK/Erk. Importantly, it was noted that Ras significantly augmented both the γ-IR-induced NF-κB activity and the γ-IR-induced CD23 expression. Together these results suggest that while γ-IR and Ras both contribute to the upregulation of CD23 expression via NF-κB Raf or Erk is not involved in γ-IR-induced NF-κB activation.

This study is supported in part by research grants from MOST (2003-0318-000) and KOSEF (R01-1999-000-00138-0).