Cooperative interaction of NF‐κB and C/EBP binding sites is necessary for manganese superoxide dismutase gene transcription mediated by lipopolysaccharide and interferon‐γ

Abstract

Expression of the manganese superoxide dismutase (Mn-SOD) is induced by pro-inflammatory cytokines. We investigated the cis-acting elements within a tumor necrosis factor-responsive element (TNFRE) which was identified in the second intron of the murine Mn-SOD gene. Site-directed mutagenesis, reporter plasmid transfection studies and electrophoretic mobility shift assays demonstrated that inducible transcription factors enhanced the transcriptional activity of the Mn-SOD gene through the TNFRE. The cooperation between proteins binding to the newly identified NF-U UB and C/ EBP sites led to synergistic gene transcription. This report provides the first evidence that cooperation between two distinct cis-acting elements may be required for induction of Mn-SOD gene expression mediated by lipopolysaccharide and interferon-Q Q.z 1999 Federation of European Biochemical Societies.

Identification of Nucleophosmin as an NF-κB Co-activator for the Induction of the Human SOD2 Gene

“…We also demonstrate that activation of CEBP/␤ in addition to NF-B is a mechanism leading to synergistic induction of MnSOD by PMA and cytokines (41). Our results are also consistent with reports that demonstrate that NF-B is a potential transcription factor activated simultaneously with other transcription factors, such as C/EBP upon stimulation by cytokines, producing cross-talk between them to maximize gene induction (30,48). In this present report we confirm the synergistic induction of the SOD2 gene in a hepatocarcinoma cell line, and extend the observation to include p50 and p65, c-Rel, another NF-B protein of the Rel family, in the synergistic induction process.…”

The Tumor Necrosis Factor α-dependent Activation of the Human Mediterranean Fever (MEFV) Promoter Is Mediated by a Synergistic Interaction between C/EBPβ and NFκB p65

“…Indeed, it has been reported that cotransfection of NFB p65 and C/EBP␤ induces a synergistic activation of the interleukin (IL)-6 and IL-8 promoters (28,31,32), by means of a direct interaction between the b-Zip domain of C/EBP␤ and the Rel homology domain of NFB p65 (28). In very few instances, such a synergistic effect of NFB p65 and C/EBP␤ on gene transcription has been reported in response to inflammatory mediators: this is the case for genes encoding the manganese superoxide dismutase (33), the coagulation factor VIII (34), and the serum amyloid A1 protein (35,36), in response to LPS/interferon-␥, LPS, and LPS/IL-1/IL-6, respectively. Interestingly, a similar synergy between NFB p65 and C/EBP␤, but in response to TNF␣, has been observed in the transcriptional regulation of the cyclooxygenase-2 (37), the granulocyte colony-stimulating factor (38), and the intercellular adhesion molecule-1 (39,40) genes, three sequences that, like MEFV, are expressed by cells directly involved in inflammatory processes.…”

Transcriptional control of granulocyte and monocyte development

“…p52 partially substitutes for the lack of p50 and cRel for the lack of p65 (Hoffmann et al, 2003). C/EBPb and NF-kB cooperatively bind and activate the IL-6, IL-8, G-CSF, serum amyloid, intercellular adhesion molecule 1, superoxide dismutase and Mediterranean fever promoters during the inflammatory response in myeloid and other cells (Dunn et al, 1994;Kunsch et al, 1994;Xia et al, 1997;Maehara et al, 1999;Papin et al, 2003). Co-immunoprecipitation demonstrates interaction of bacterially expressed C/EBPa or C/EBPb with bacterially expressed or in vitro translated p50 or p65, mapping to the bZIP domain of C/EBP and to the Rel homology domain of p65 (Matsusaka et al, 1993;Stein et al, 1993).…”