Transcriptional regulation of 1-cys peroxiredoxin by the proto-oncogene protein DEK

Abstract

Abstract. The nuclear phosphoprotein deK is abundantly present in cells and is implicated in diseases including leukemia and autoimmune disorders. deK has three highly acidic amino acid domains and inhibits histone acetyltransferase activity by binding directly to histones. in a previous study, differentially regulated proteins under deK knockdown conditions, including the up-regulated protein 1-cys peroxiredoxin (1-cys Prx), were identified by proteome analysis. Here, an in vivo reporter assay with short hairpin rna-mediated deK knockdown revealed that deK negatively regulated 1-cys Prx transcription, and that the nF-κB subunit p65 had a synergistic effect on this deK-mediated repression. Both proteins are recruited to the 1-cys Prx promoter region and regulate its transcription. our study demonstrates that deK modulates the transcriptional regulation of the target gene through protein interaction with other regulatory proteins. IntroductionThe DEK protein was first identified in a specific chromosomal translocation t(6;9)(p23;q34) in an acute myelogenous leukemia, which results in the formation of a fusion gene with the can nucleoporin protein nuP214 (1). This translocated fusion gene makes a fusion protein, in which part of the n-terminal (1-349 amino acids) of deK is fused with part of the c-terminal (813-2,090 amino acids) of can. The deK protein, as a phosphoprotein, is an abundantly and ubiquitously expressed nuclear protein with two functional domains (SaP and dna binding/multimerization), several phosphorylation sites and three highly acidic domains (2,3). deK binds dna and induces deK-deK multimerization in a phosphorylation-dependent manner (4). a recent report showed that a highly acidic domain in deK inhibits histone acetyltransferase (HAT) activity through histone binding (2). It has been revealed that DEK influences chromatin remodeling through the alteration of chromatin topology (5,6). deK also regulates transcriptional activity by recruiting transcriptional co-repressors, such as hdaxx and histone deacetylase-2, to chromatin (7).deK is also involved in carcinogenesis and autoimmune diseases, such as systemic lupus erythematosus, juvenile rheumatoid arthritis and ataxia telangiectasia (8). a recent proteomic analysis revealed that deK knockdown up-regulated 1-cys peroxiredoxin (1-cys Prx) (Prx 6) and caused the hyperacetylation of histones around the 1-cys Prx promoter (9).1-cys Prx is one of six Prx isoforms, and is expressed in various tissues -in particular liver tisses -related to the protection of cellular oxidative stresses (10).nF-κB is a transcription factor with multiple biological functions, including immune and inflammatory response, cell growth and differentiation, and the suppression of apoptosis (11). The nF-κB family consists of five members, p65/RelA, p50 (p105), p52 (p100), relB and c-rel (12). a previous study showed that the p65 subunit of nF-κB interacts with deK (13).In this study, we identified the negative regulatory role of deK in 1-cys Prx transcription: its knockdown re...