NF-E2 domination over Nrf2 promotes ROS accumulation and megakaryocytic maturation

Motohashi, Hozumi; Kimura, Momoko; Fujita, Rie; Inoue, A.; Pan, Xiaoqing; Takayama, M.; Katsuoka, Fumiki; Aburatani, Hiroyuki; Bresnick, Emery H.; Yamamoto, Masayuki

doi:10.1182/blood-2009-05-223107

Cited by 87 publications

(103 citation statements)

References 42 publications

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“…Genetic evidence indicates that the p45-small Maf heterodimer, NF-E2, is required for megakaryocyte proliferation (25,34), cytoplasmic maturation (45), proplatelet formation (24,37), and platelet gene expression (2,6,34,48). Since there are three functionally redundant small Maf proteins, most tissues and cell lineages display little or no defects upon deleting a single gene encoding small Maf proteins (36,44).…”

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confidence: 99%

Molecular Determinants for Small Maf Protein Control of Platelet Production

Motohashi

Fujita

Takayama

et al. 2011

Molecular and Cellular Biology

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MafG and p45 possess basic region-leucine zipper (bZip) domains and form a heterodimer called NF-E2, a key regulator of megakaryopoiesis. NF-E2 binds to the Maf recognition element (MARE) and activates transcription of many platelet genes. Since the bZip domain, which mediates DNA binding and heterodimerization, is the only functional domain established for MafG, it has been assumed that MafG is required only for p45 binding to MARE and to facilitate p45-mediated transcriptional activation. Analysis of the C-terminal region of MafG, which is distinct from the bZip domain, revealed that this region contains a nuclear matrix-targeting signal. We used a transgenic complementation rescue assay to delineate the function of the MafG C terminus in vivo. Transgenic mice expressing a mutant MafG protein lacking the C terminus (MafG⌬C) were crossed into a MafG-null background. The compound mutant mice displayed severe thrombocytopenia and splenomegaly, which phenocopied p45-null mice. The MafG C terminus is essential for proplatelet formation and platelet gene activation but not for p45 binding to MARE. These results demonstrate that the MafG C terminus is required for NF-E2 function and suggest that efficient targeting of NF-E2 to a specific nuclear scaffold is important to achieve high-level activity.

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Molecular Determinants for Small Maf Protein Control of Platelet Production

Motohashi

Fujita

Takayama

et al. 2011

Molecular and Cellular Biology

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“…These mice display thrombocytopenia associated with impaired maturation of megakaryocytes, subsequently developing myelofibrosis. Considering that NF-E2 is critical for thrombopoiesis (Motohashi et al 2010), these results suggest that Bach1 acts as a transcriptional repressor in the regulation of MARE-dependent genes in megakaryocytes as well. …”

Section: Bach1 In the Regulation Of Erythropoiesis And Megakaryopoiesismentioning

confidence: 99%

Wearing Red for Signaling: The Heme-Bach Axis in Heme Metabolism, Oxidative Stress Response and Iron Immunology

Igarashi

Watanabe-Matsui

2014

Tohoku J. Exp. Med.

104

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The connection between gene regulation and metabolism is an old issue that warrants revisiting in order to understand both normal as well as pathogenic processes in higher eukaryotes. Metabolites affect the gene expression by either binding to transcription factors or serving as donors for post-translational modification, such as that involving acetylation and methylation. The focus of this review is heme, a prosthetic group of proteins that includes hemoglobin and cytochromes. Heme has been shown to bind to several transcription factors, including Bach1 and Bach2, in higher eukaryotes. Heme inhibits the transcriptional repressor activity of Bach1, resulting in the derepression of its target genes, such as globin in erythroid cells and heme oxygenase-1 in diverse cell types. Since Bach2 is important for class switch recombination and somatic hypermutation of immunoglobulin genes as well as regulatory and effector T cell differentiation and the macrophage function, the heme-Bach2 axis may regulate the immune response as a signaling cascade. We discuss future issues regarding the topic of the iron/heme-gene regulation network based on current understanding of the heme-Bach axis, including the concept of "iron immunology" as the synthesis of the iron metabolism and the immune response.

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“…16,17 Accordingly, we hypothesized that defective BLVRB S111L redox coupling could affect ROS accumulation, a requisite upstream signaling messenger of MK differentiation, 31,32 and stem cell quiescence during migration from hypoxic (low ROS) osteoblastic to oxygen-rich (high ROS) vascular niches. 33,34 Hematopoietic-derived (CD34 1 ) iPSCs infected with individual lentiviruses established that iPSC/BLVRB WT cells (expressing BLVRB approximately twofold greater than control) retained enhanced redox activity (P 5 .001) compared with both control and iPSC/BLVRB S111L cells; redox coupling in iPSC/BLVRB S111L paralleled that of control iPSCs ( Figure 5A).…”

Section: Blvrb Redox Function Alters Cellular Ros Accumulationmentioning

confidence: 99%