title: NRH:quinone oxidoreductase 2 (NQO2) protein competes with the 20 S proteasome to stabilize transcription factor CCAAT enhancer-binding protein α (C/EBPα), leading to protection against γ radiation-induced myeloproliferative disease.
abstract: NRH:quinone oxidoreductase 2 (NQO2) is a flavoprotein that protects cells against radiation and chemical-induced oxidative stress. Disruption of the NQO2 gene in mice leads to γ radiation-induced myeloproliferative diseases. In this report, we showed that the 20 S proteasome and NQO2 both interact with myeloid differentiation factor CCAAT-enhancer-binding protein α (C/EBPα). The interaction of the 20 S proteasome with C/EBPα led to the degradation of C/EBPα. NQO2, in the presence of its cofactor NRH, protected C/EBPα against 20 S degradation. Deletion and site-directed mutagenesis demonstrated that NQO2 and 20 S competed for the same binding region of S(268)GAGAGKAKKSV(279) in C/EBPα. Exposure of mice and HL-60 cells to γ radiation enhanced the levels of NQO2, which led to an increased NQO2 interaction with C/EBPα and decreased 20 S interaction with C/EBPα. NQO2 stabilization of C/EBPα was independent of NQO1, even though both interacted with the same C/EBPα domain. NQO2(-/-) mice, deficient in NQO2, failed to stabilize C/EBPα. This contributed to the development of γ radiation-induced myeloproliferative disease in NQO2(-/-) mice.
authors.affiliation: From the Department of Pharmacology, University of Maryland School of Medicine, Baltimore, Maryland 21201.
authors.forename: Junkang
authors.initials: J
authors.lastname: Xu
authors.forename: Brad Allen
authors.initials: BA
authors.lastname: Patrick
authors.forename: Anil K
authors.initials: AK
authors.lastname: Jaiswal
mesh_terms: D000818:Animals; D001665:Binding Sites; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000528:radiation effects; D005720:Gamma Rays; D018922:HL-60 Cells; D006801:Humans; D051379:Mice; D009196:Myeloproliferative Disorders / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism* / Q000528:radiation effects; D011485:Protein Binding; D060066:Protein Interaction Maps; D059748:Proteolysis; D011808:Quinone Reductases / Q000235:genetics / Q000378:metabolism*; D011837:Radiation-Protective Agents
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D011837:Radiation-Protective Agents; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse; C419642:NRH - quinone oxidoreductase2; D011808:Quinone Reductases; D046988:Proteasome Endopeptidase Complex
keywords: 20 S Proteasome; C/EBPα; Chemoprevention; Myeloproliferative Diseases; NQO2; Protein Degradation; Protein Stability; Protein-Protein Interactions; Signal Transduction