Abstract 3074: NAD(P)H:quinone oxidoreductase 1 stabilizes C/EBPα from 20S proteasomal degradation leading to protection against myeloproliferative disease

Abstract

Abstract NAD(P)H:quinone oxidoreductase 1 (NQO1) is a flavoprotein that protects cells against radiation and chemical induced oxidative stress. Disruption of NQO1 gene in mice leads to α-radiation-induced myeloproliferative disease. In the present study, we demonstrate that myeloid differentiation factor C/EBPα is degraded by 20S proteasome, and that NQO1 could salvage C/EBPα from 20S proteasomal degradation. Coimmunoprecipitation studies showed that NQO1, C/EBPα and 20S all interacted with each other. Deletion and site-directed mutagenesis studies demonstrated that NQO1 and 20S competed for the same binding region in C/EBPβ. Mutagenesis study also revealed that NQO1Y127/Y129 required for NADH binding is essential for NQO1 stabilization of C/EBPβ. Exposure of mice and HL-60 cells to α-radiation led to increased NQO1 and decreased 20S interaction with C/EBPβ, which resulted in stabilization of C/EBPα and protection against α-radiation-induced myeloproliferative diseases. This mechanism might provide day-to-day protection to bone marrow against adverse effects of radiation and chemical exposure, which has significant effect on individuals carrying hetero- or homozygous NQO1P187S mutation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3074. doi:1538-7445.AM2012-3074