Impaired megakaryopoiesis and behavioral defects in<i>mafG</i>-null mutant mice

Shavit, Jordan A.; Motohashi, Hozumi; Onodera, Ko; Akasaka, Jun Etsu; Yamamoto, Masayuki; Engel, James Douglas

doi:10.1101/gad.12.14.2164

Cited by 102 publications

(135 citation statements)

References 34 publications

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“…We previously isolated phage clones containing the mouse mafG locus and mapped coding exons II and III but did not determine the nature of the noncoding first exon(s) (13). Therefore, we first performed 5Ј-RACE to determine first exon(s) utilized by the mafG gene and identified three (designated Ia, Ib, and Ic) ( Fig.…”

Section: Nrf2 Activates Mafg Through An Are 4485mentioning

confidence: 99%

“…The functions of small Maf proteins are compensatory and provide partially overlapping redundancy, since small maf single mutant mice (mafG Ϫ/Ϫ , mafK Ϫ/Ϫ , and mafF Ϫ/Ϫ ) showed mild or subtle phenotypes (12)(13)(14), whereas small maf compound mutant mice (mafG Ϫ/Ϫ :mafF Ϫ/Ϫ and mafG Ϫ/Ϫ :mafF Ϫ/Ϫ :mafK Ϫ/Ϫ ) displayed a greater number of and more profound deficiencies (15, 16).…”

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confidence: 99%

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Nrf2 Transcriptionally Activates the mafG Gene through an Antioxidant Response Element

Katsuoka

Motohashi

Engel

et al. 2005

Journal of Biological Chemistry

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107

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Nrf2 accumulates in nuclei upon exposure to oxidative stress, heterodimerizes with a small Maf protein, and activates the transcription of stress target genes through antioxidant response elements (AREs). We found that diethyl maleate (DEM), a well known activator of Nrf2, induces one of the small Maf genes, mafG. To elucidate roles MafG might play in the oxidative stress response, we examined transcriptional regulation of the mouse mafG gene. MafG utilizes three independent first exons that are each spliced to second and third coding exons. Among the small maf genes, mafG showed the strongest response to DEM, and of the three first exons, the highest -fold induction was seen with the proximal first exon (Ic). Importantly, one ARE (Ic-ARE) is conserved in the promoter flanking exon Ic of the human and mouse mafG genes. The Nrf2/MafG heterodimer bound the Ic-ARE and activated transcription, whereas DEM failed to activate mafG in nrf2-null mutant cells. Chromatin immunoprecipitation further revealed that both Nrf2 and small Maf proteins associate with the Ic-ARE in vivo. These results demonstrate that mafG is itself an ARE-dependent gene that is regulated by an Nrf2/small Maf heterodimer and suggest the presence of an autoregulatory feedback pathway for mafG transcriptional regulation.

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Section: Nrf2 Activates Mafg Through An Are 4485mentioning

confidence: 99%

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confidence: 99%

Nrf2 Transcriptionally Activates the mafG Gene through an Antioxidant Response Element

Katsuoka

Motohashi

Engel

et al. 2005

Journal of Biological Chemistry

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107

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“…Genetic and biochemical studies have revealed that the small Maf-p45 heterodimer, which is also known as NF-E2, serves as an indispensable transcriptional activator for terminal megakaryocyte differentiation (17,24,29,31). The megakaryocytes of p45-null mutant mice proliferate and differentiate in response to thrombopoietin, without practically any proplatelet generation.…”

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confidence: 99%

MafG Sumoylation Is Required for Active Transcriptional Repression

Motohashi

Katsuoka

Miyoshi

et al. 2006

Molecular and Cellular Biology

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A straightforward mechanism for eliciting transcriptional repression would be to simply block the DNA binding site for activators. Such passive repression is often mediated by transcription factors that lack an intrinsic repressor activity. MafG is a bidirectional regulator of transcription, a repressor in its homodimeric state but an activator when heterodimerized with p45. Here, we report that MafG is conjugated to SUMO-2/3 in vivo. To clarify the possible physiological role(s) for sumoylation in regulating MafG activity, we evaluated mutant and wild-type MafG in transgenic mice and cultured cells. Whereas sumoylation-deficient MafG activated p45-dependent transcription normally and did not affect heterodimer activity, repression by the sumoylation-deficient MafG mutant was severely compromised in vivo. Furthermore, the SUMO-dependent repression activity of MafG was sensitive to histone deacetylase inhibition. Thus, repression by MafG is not achieved through simple passive repression by competing for the activator binding site but requires sumoylation, which then mediates transcriptional repression through recruitment of a repressor complex containing histone deacetylase activity.

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“…[1][2][3][4] It is composed of two subunits (p45 and p18), each of which contains a basic region-leucine zipper DNA binding domain. 3,5 The p18 subunit is a small Maf protein, [6][7][8] namely MafG, which partners the p45 subunit (ie p45 NF-E2) in megakaryocyte (MK) development. 8 The heterodimers of p45 and small Mafs can activate transcription via Mares (ie Maf recognition elements: TGCTGAC(T/GT)CAGCA), whereas the homodimers of small Mafs form repressors that act on the same sites.…”

Section: Introductionmentioning

confidence: 99%

“…3,5 The p18 subunit is a small Maf protein, [6][7][8] namely MafG, which partners the p45 subunit (ie p45 NF-E2) in megakaryocyte (MK) development. 8 The heterodimers of p45 and small Mafs can activate transcription via Mares (ie Maf recognition elements: TGCTGAC(T/GT)CAGCA), whereas the homodimers of small Mafs form repressors that act on the same sites. 6,9 Acetilation by cAMP-response element-binding protein (CREB)-binding protein (CBP) augments DNA binding of p45 NF-E2.…”

Section: Introductionmentioning

confidence: 99%

Nuclear factor-erythroid 2 (NF-E2) expression in normal and malignant megakaryocytopoiesis

et al. 2002

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Although the transcription factor nuclear factor-erythroid 2 (NF-E2) is known to be functionally linked to the megakaryocytic lineage, little is known about its role in malignant megakaryocytes. We used real-time RT-PCR and Western blotting to investigate expression of NF-E2 and its partner, MafG, in CD34-derived normal (five cases) and malignant megakaryocytes from essential thrombocythemia (ET) patients (eight cases) and in megakaryoblastic cell lines. We also quantitated the mRNA of the thromboxane synthase (TXS) gene, which is directly regulated by NF-E2. Although real-time RT-PCR showed that both a and f NF-E2 isoforms were significantly reduced with respect to the normal counterpart both in ET megakaryocytes and in cell lines (P р 0.01), western blotting revealed decreased NF-E2 protein expression only in the latter. However, both the NF-E2a/MafG mRNA ratio (P р 0.01) and TXS (P р 0.01) mRNA expression were significantly reduced in megakaryocytes from ET patients and cell lines with respect to healthy subjects. These two findings provide strong indirect evidence of altered activity of the a isoform of NF-E2 in malignant megakaryocytes, raising the possibility that NF-E2 could play a role in megakaryocyte transformation.

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Impaired megakaryopoiesis and behavioral defects inmafG-null mutant mice

Cited by 102 publications

References 34 publications

Nrf2 Transcriptionally Activates the mafG Gene through an Antioxidant Response Element

Nrf2 Transcriptionally Activates the mafG Gene through an Antioxidant Response Element

MafG Sumoylation Is Required for Active Transcriptional Repression

Nuclear factor-erythroid 2 (NF-E2) expression in normal and malignant megakaryocytopoiesis

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