SMAD1 and SMAD5 Expression Is Coordinately Regulated by FLI1 and GATA2 during Endothelial Development

Marks-Bluth, Jonathon; Khanna, Anchit; Chandrakanthan, Vashe; Thoms, Julie A.I.; Bee, Thomas; Eich, Christina; Kang, Young Chan; Knezevic, Kathy; Qiao, Qiao; Fitch, Simon R.; Oxburgh, Leif; Ottersbach, Katrin; Dzierzak, Elaine; Bruijn, Marella F. T. R. de; Pimanda, John E.

doi:10.1128/mcb.00239-15

Cited by 12 publications

(6 citation statements)

References 39 publications

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“…As suggested, bone morphogenetic protein (BMP)/Smad signaling pathway promote the vascular development [16]. As a key mediator of BMP/Smad pathway, Smad5 can act as a target of microRNA to suppress the endothelial development and thereby the angiogenesis, a must for tumor progression and tumor metastases [17, 18]. Interestingly, Smad5 is a well-accepted suppressive gene in osteoclast differentiation and thereby decreases resorption pits [19].…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-93-5p may participate in the formation of morphine tolerance in bone cancer pain mouse model by targeting Smad5

Xiao

Lou

et al. 2016

Oncotarget

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ObjectiveIn this study, we aim to find out the role of microRNA-93-5p (miR-93) and Smad5 in morphine tolerance in mouse models of bone cancer pain (BCP).ResultsAt 7 days after injection of morphine, the PMWT showed no significant difference between the morphine model group and the saline model group (P < 0.05), suggesting that morphine tolerance had formed in the morphine model group. The morphine model group had higher miR-93 expression and lower Smad5 mRNA expression than the saline model group. Smad5 is a downstream target gene of miR-93. At 7, 9 and 14 days after injection of lentiviruses, the L/anti-miR-93 group had the lowest PMWTs, while the Smad5 shRNA group presented the highest PMWTs among these five groups (all P < 0.05).MethodsWe built mouse models of BCP and morphine tolerance and recorded 50% PMWT. After 6 days of modeling, we set saline control group, morphine control, saline model group and morphine model group (morphine tolerance emerged). We performed luciferase reporter gene assay to verify the relation between miR-93 and Smad5. After lentivirus transfection, the mice with morphine tolerance were assigned into L/anti-miR-93 group, Smad5 shRNA group, L/anti-miR-93 + Smad5 shRNA group, blank group and PBS control group. RT-qPCR, Western Blot assay and immumohistochemical staining were performed to observe the changes of miR-93 and Smad5.ConclusionUp-regulation of miR-93 may contribute to the progression of morphine tolerance by targeting Smad5 in mouse model of BCP.

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Section: Introductionmentioning

confidence: 99%

MicroRNA-93-5p may participate in the formation of morphine tolerance in bone cancer pain mouse model by targeting Smad5

Xiao

Lou

et al. 2016

Oncotarget

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“…These results suggest that the products of those genes may be responsible for the phenotypes of the qualitative defect of GATA2. In particular, Smad5 has been shown to be a GATA2-target gene and a key regulator of BMP signaling 52 , 54 , 55 , which supports HSC heterogeneity and lineage output decisions in the myeloid and lymphoid axes 56 . We envisage that perturbations in the expression of these GATA2 target genes may disturb the proliferation and differentiation of hematopoietic lineage cells.…”

Section: Discussionmentioning

confidence: 99%

Heterozygous variants in GATA2 contribute to DCML deficiency in mice by disrupting tandem protein binding

et al. 2022

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Accumulating lines of clinical evidence support the emerging hypothesis that loss-of-function mutations of GATA2 cause inherited hematopoietic diseases, including Emberger syndrome; dendritic cell, monocyte B and NK lymphoid (DCML) deficiency; and MonoMAC syndrome. Here, we show that mice heterozygous for an arginine-to-tryptophan substitution mutation in GATA2 (G2R398W/+), which was found in a patient with DCML deficiency, substantially phenocopy human DCML deficiency. Mice heterozygous for the GATA2-null mutation (G2-/+) do not show such phenotypes. The G2R398W protein possesses a decreased DNA-binding affinity but obstructs the function of coexpressed wild-type GATA2 through specific cis-regulatory regions, which contain two GATA motifs in direct-repeat arrangements. In contrast, G2R398W is innocuous in mice containing single GATA motifs. We conclude that the dominant-negative effect of mutant GATA2 on wild-type GATA2 through specific enhancer/silencer of GATA2 target genes perturbs the GATA2 transcriptional network, leading to the development of the DCML-like phenotype. The present mouse model provides an avenue for the understanding of molecular mechanisms underlying the pathogenesis of GATA2-related hematopoietic diseases.

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“…GATA1 and GATA2 colocalize on chromatin with other transcription factors and coregulators at sites that often, but not always, contain E-box-spacer-WGATAR composite elements (16,61,(83)(84)(85)(86)(87). The ETS factor Fli1 occupies these sites and is implicated in GATA1-and GATA2-mediated activation (88,89). Although the ETS factor PU.1 can antagonize GATA1 or GATA2 (71,90,91), it can cooperate with GATA2 in activation (92).…”

Section: Discussionmentioning

confidence: 99%

Pathogenic human variant that dislocates GATA2 zinc fingers disrupts hematopoietic gene expression and signaling networks

Jung¹,

Shen²,

Botten³

et al. 2023

Journal of Clinical Investigation

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Although certain human genetic variants are conspicuously loss-of-function, decoding the impact of many variants is challenging. Previously, we described a leukemia predisposition syndrome (GATA2-deficiency) patient with a germline GATA2 variant that inserts nine amino acids between the two zinc fingers (9aa-Ins). Here, we conducted mechanistic analyses using genomic technologies and a genetic rescue system with Gata2 enhancer-mutant hematopoietic progenitor cells to compare how GATA2 and 9aa-Ins function genome-wide. Despite nuclear localization, 9aa-Ins was severely defective in occupying and remodeling chromatin and regulating transcription. Variation of the inter-zinc finger spacer length revealed that insertions were more deleterious to activation than repression. GATA2-deficiency generated a lineagediverting gene expression program and a hematopoiesis-disrupting signaling network in progenitors with reduced Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) and elevated Interleukin-6 (IL-6) signaling. As insufficient GM-CSF signaling causes pulmonary alveolar proteinosis and excessive IL-6 signaling promotes bone marrow failure, GATA2deficiency patient phenotypes, these results inform mechanisms underlying GATA2-linked pathologies.

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SMAD1 and SMAD5 Expression Is Coordinately Regulated by FLI1 and GATA2 during Endothelial Development

Cited by 12 publications

References 39 publications

MicroRNA-93-5p may participate in the formation of morphine tolerance in bone cancer pain mouse model by targeting Smad5

MicroRNA-93-5p may participate in the formation of morphine tolerance in bone cancer pain mouse model by targeting Smad5

Heterozygous variants in GATA2 contribute to DCML deficiency in mice by disrupting tandem protein binding

Pathogenic human variant that dislocates GATA2 zinc fingers disrupts hematopoietic gene expression and signaling networks

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