MGRN1

MGRN1
  • 文章类型: Journal Article
    房间隔缺损的临床表现和处理的相对简单性掩盖了发育发病机理的复杂性。这里,我们描述了房间隔的解剖发育和静脉回流到心房腔。实验模型表明,突变和自然发生的遗传变异如何影响发育步骤,从而导致椭圆形窝内的缺陷,所谓的secundum缺陷,或其他心房通信,如静脉窦缺损或原孔缺损。
    The relative simplicity of the clinical presentation and management of an atrial septal defect belies the complexity of the developmental pathogenesis. Here, we describe the anatomic development of the atrial septum and the venous return to the atrial chambers. Experimental models suggest how mutations and naturally occurring genetic variation could affect developmental steps to cause a defect within the oval fossa, the so-called secundum defect, or other interatrial communications, such as the sinus venosus defect or ostium primum defect.
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  • 文章类型: Journal Article
    桃花素环指1是由颜色基因MGRN1编码的E3-泛素连接酶。我们先前的体外和体内研究表明,小鼠黑色素瘤细胞中Mgrn1缺失诱导细胞分化和粘附,减少了细胞运动和对I型胶原的侵袭,和体内模型中的肺定植。这里,我们研究了MGRN1对人黑色素瘤细胞形态的作用,参与EMT样转变的基因/蛋白质的粘附和表达。我们证明了野生型BRAF人黑色素瘤细胞在胶原蛋白I上采用了聚类样形态,永久的MGRN1废除导致更大的细胞簇。增强的细胞间粘附主要是由E-cadherin的诱导和与β-catenin的更高的共定位介导的。E-钙粘蛋白的转录上调可能是通过下调ZEB1阻遏物而发生的。最后,下拉测定显示在缺乏MGRN1的情况下CDC42的活化降低,其在E-钙黏着蛋白沉默后恢复。总的来说,这些发现突出了一个新的MGRN1依赖性途径调节黑色素瘤细胞的形状,运动性,和入侵潜力。
    Mahogunin Ring Finger 1 is an E3-ubiquitin ligase encoded by the color gene MGRN1. Our previous in vitro and in vivo studies demonstrated that Mgrn1 deletion in mouse melanoma cells induced cell differentiation and adhesion, and decreased cell motility and invasion on collagen I, and lung colonization in an in vivo model. Here, we investigated the role of MGRN1 on human melanoma cell morphology, adhesion and expression of genes/proteins involved in an EMT-like transition. We demonstrated that wild-type BRAF human melanoma cells adopted a clustering-like morphology on collagen I, with permanent MGRN1 abrogation resulting in bigger cell clusters. Enhanced intercellular adhesion was mostly mediated by induction of E-cadherin and higher co-localization with β-catenin. Transcriptional upregulation of E-cadherin likely occurred through downregulation of the ZEB1 repressor. Finally, pulldown assays showed reduced activation of CDC42 in the absence of MGRN1, which was reverted after E-cadherin silencing. Overall, these findings highlight a new MGRN1-dependent pathway regulating melanoma cell shape, motility, and invasion potential.
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  • 文章类型: Journal Article
    红木无名指1(MGRN1),E3泛素,参与几个生理和神经病理学过程。尽管mgrn1mRNA广泛分布于中枢神经系统(CNS),有关其细胞和亚细胞定位的详细信息尚不清楚,其生理作用尚不清楚。在这项研究中,我们的目的是使用新产生的针对MGRN1的抗体来确定MGRN1在小鼠CNS中的分布.我们发现MGRN1蛋白在大多数神经元细胞体中表达。在中枢神经系统不同区域的灰质神经纤维中也观察到强烈的MGRN1表达,包括主嗅觉灯泡,大脑皮层,尾状,壳核,丘脑核,下丘脑核,内侧隆起,上丘,海马体,齿状回,和脊髓。相反,在胶质细胞中未观察到MGRN1表达。双重荧光和免疫电子显微镜分析显示MGRN1在突触前和神经元线粒体外膜附近的细胞内分布。这些发现表明MGRN1在整个CNS中更广泛地表达;此外,MGRN1的细胞内表达提示其可能在突触和线粒体功能中起重要作用。
    Mahogunin ring finger 1 (MGRN1), an E3 ubiquitin, is involved in several physiological and neuropathological processes. Although mgrn1 mRNA is widely distributed in the central nervous system (CNS), detailed information on its cellular and subcellular localization is lacking and its physiological role remains unclear. In this study, we aimed to determine the distribution of MGRN1 in the mouse CNS using a newly produced antibody against MGRN1. We found that the MGRN1 protein was expressed in most neuronal cell bodies. An intense MGRN1 expression was also observed in the neuropil of the gray matter in different regions of the CNS, including the main olfactory bulb, cerebral cortex, caudate, putamen, thalamic nuclei, hypothalamic nuclei, medial eminence, superior colliculus, hippocampus, dentate gyrus, and spinal cord. Contrastingly, no MGRN1 expression was observed in glial cells. Double fluorescence and immunoelectron microscopic analyses revealed the intracellular distribution of MGRN1 in pre-synapses and near the outer membrane of the mitochondria in neurons. These findings indicate that MGRN1 is more widely expressed throughout the CNS; additionally, the intracellular expression of MGRN1 suggests that it may play an important role in synaptic and mitochondrial functions.
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  • 文章类型: Journal Article
    旁分泌细胞-细胞通讯是所有发育过程的核心,从细胞多样化到模式和形态发生。信号强度的精确校准对于成人胚胎发生和组织维持期间组织形成的保真度至关重要。膜束缚的泛素连接酶可以通过调节细胞表面的信号受体的丰度来控制靶细胞对分泌的配体的敏感性。我们讨论了信号传导中这种新兴概念的两个例子:(1)响应于R-spondin配体调节WNT和骨形态发生蛋白受体丰度的跨膜泛素连接酶ZNRF3和RNF43,以及(2)控制Hedgehog和黑皮质素受体丰度的膜募集泛素连接酶MGRN1。我们专注于这些系统的机械逻辑,由AlphaFold启用的结构和蛋白质相互作用模型说明。我们建议膜束缚的泛素连接酶在重塑细胞表面蛋白质组以控制不同生物过程中对细胞外配体的反应中起着广泛的作用。
    Paracrine cell-cell communication is central to all developmental processes, ranging from cell diversification to patterning and morphogenesis. Precise calibration of signaling strength is essential for the fidelity of tissue formation during embryogenesis and tissue maintenance in adults. Membrane-tethered ubiquitin ligases can control the sensitivity of target cells to secreted ligands by regulating the abundance of signaling receptors at the cell surface. We discuss two examples of this emerging concept in signaling: (1) the transmembrane ubiquitin ligases ZNRF3 and RNF43 that regulate WNT and bone morphogenetic protein receptor abundance in response to R-spondin ligands and (2) the membrane-recruited ubiquitin ligase MGRN1 that controls Hedgehog and melanocortin receptor abundance. We focus on the mechanistic logic of these systems, illustrated by structural and protein interaction models enabled by AlphaFold. We suggest that membrane-tethered ubiquitin ligases play a widespread role in remodeling the cell surface proteome to control responses to extracellular ligands in diverse biological processes.
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  • 文章类型: Journal Article
    异常的DNA甲基化被认为在上皮性卵巢癌(EOC)的化学耐药性中起关键作用。在这项研究中,在高级别浆液性卵巢癌(HGSOC)患者中,我们探讨了桃花素环指1(MGRN1)基因启动子高甲基化与原发性化疗耐药和临床结局之间的关系.MALDI-TOF质谱分析揭示了MGRN1上游区域的高甲基化与HGSOC患者的铂耐药性之间的强关联。Spearman相关分析显示MGRN1甲基化水平与其在HGSOC中的表达呈显著负相关。体外分析证明MGRN1的敲低降低了细胞对顺铂的敏感性,并且EGR1的表达在MGRN1表达水平低的SKOV3细胞中显著降低。同样,铂耐药HGSOC患者EGR1mRNA表达较低,与MGRN1mRNA表达呈正相关。Kaplan-Meier分析显示MGRN1启动子区的高甲基化和MGRN1的低表达与HGSOC患者的较差生存率相关。在多变量模型中,MGRN1低表达是预测预后不良的独立因素。此外,Kaplan-Meier也证实EGR1的低表达与HGSOC患者的不良预后显著相关。MGRN1启动子区的高甲基化和MGRN1的低表达与HGSOC患者的铂类耐药和不良预后有关。可能是通过改变EGR1表达。
    Aberrant DNA methylation is considered to play a critical role in the chemoresistance of epithelial ovarian cancer (EOC). In this study, we explored the relationship between hypermethylation of the Mahogunin Ring Finger 1 (MGRN1) gene promoter and primary chemoresistance and clinical outcomes in high-grade serous ovarian cancer (HGSOC) patients. The MALDI-TOF mass spectrometry assays revealed a strong association between hypermethylation of the MGRN1 upstream region and platinum resistance in HGSOC patients. Spearman\'s correlation analysis revealed a significantly negative connection between the methylation level of MGRN1 and its expression in HGSOC. In vitro analysis demonstrated that knockdown of MGRN1 reduced the sensitivity of cells to cisplatin and that expression of EGR1 was significantly decreased in SKOV3 cells with low levels of MGRN1 expression. Similarly, EGR1 mRNA expression was lower in platinum-resistant HGSOC patients and was positively correlated with MGRN1 mRNA expression. Kaplan-Meier analyses showed that high methylation of the MGRN1 promoter region and low expression of MGRN1 were associated with worse survival of HGSOC patients. In multivariable models, low MGRN1 expression was an independent factor predicting poor outcome. Furthermore, low expression of EGR1 was also been confirmed to be significantly related to the poor prognosis of HGSOC patients by Kaplan-Meier. The hypermethylation of the MGRN1 promoter region and low expression of MGRN1 were associated with platinum resistance and poor outcomes in HGSOC patients, probably by altering EGR1 expression.
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  • 文章类型: Journal Article
    Signaling from the melanocortin 1 receptor (MC1R), a Gs protein-coupled receptor (GPCR) crucial for melanocyte proliferation and differentiation, is regulated by cytosolic β-arrestins (ARRBs). MC1R signaling is also negatively modulated by the E3-ubiquitin ligase Mahogunin Ring Finger-1 (MGRN1), whose mutation causes hyperpigmentation, congenital heart defects and neurodegeneration in mice. We showed previously that although MC1R interacts stably with human ARRB1 or ARRB2, only ARRB2 mediates receptor desensitization and internalization. We analyzed MC1R-dependent ARRB ubiquitination, and the possible role of MGRN1. ARRB1 expressed in heterologous cells or human melanoma cells migrated in SDS-PAGE as a 55kDa protein whereas ARRB2 migrated as two major bands of apparent molecular weight near 45 and 55kDa, with an intermediate mobility band occasionally detected. These forms were related by post-translational modification rather than by proteolysis. Presence of MC1R favored expression of the 45kDa protein, the form that interacted preferentially with MC1R. MC1R also mediated poly- or multimonoubiquitination of ARRB2. Ubiquitination was agonist-independent, but required a native MC1R conformation and/or normal receptor trafficking to the plasma membrane, as it was not observed for loss-of-function MC1R variants. In a heterologous expression system, MC1R-dependent ARRB ubiquitination was enhanced by overexpression of MGRN1 and was impaired by siRNA-mediated MGRN1 knockdown thus pointing to MGRN1 as the responsible E3-ligase. Co-immunoprecipitation experiments demonstrated interaction of MGRN1 and ARRBs in the presence of MC1R, suggesting a scaffolding role for the GPCR that may determine the selectivity of E3-ubiquitin ligase engagement and the functional outcome of ARRB ubiquitination.
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  • 文章类型: Journal Article
    Health and homoeostasis are maintained by a dynamic balance between mitochondrial fission and fusion. Mitochondrial fusion machinery is largely unknown in mammals. Only a few reports have illustrated the role of Fzo1 in mitochondrial fusion known in Saccharomyces cerevisiae. We demonstrate that the ubiquitin ligase Mahogunin Ring Finger-1 (MGRN1) interacts with and constitutively ubiquitinates the mammalian homolog, Mitofusin1 (Mfn1) via K63 linkages. In mice models, loss of Mgrn1 function leads to severe developmental defects and adult-onset spongiform neurodegeneration, similar to prion diseases. The tethering of mitochondria to form the ~180kDa Mfn1 complex is independent of MGRN1-mediated ubiquitination. However, successful mitochondrial fusion requires formation of higher oligomers of Mfn1 which in turn needs GTPase activity, intact heptad repeats of Mfn1 and ubiquitination by MGRN1. Following ubiquitination, proteasomal processing of Mfn1 completes the mitochondrial fusion process. This step requires functional p97 activity. These findings suggest a sequence of events where GTPase activity of Mfn1 and tethering of adjacent mitochondria precedes its MGRN1-mediated ubiquitination and proteasomal degradation culminating in mitochondrial fusion.
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  • 文章类型: Comparative Study
    DNA methylation changes in peripheral blood DNA have been shown to be associated with solid tumors. We sought to identify methylation alterations in whole blood DNA that are associated with breast cancer (BC). Epigenome-wide DNA methylation profiling on blood DNA from BC cases and healthy controls was performed by applying Infinium HumanMethylation450K BeadChips. Promising CpG sites were selected and validated in three independent larger sample cohorts via MassARRAY EpiTyper assays. CpG sites located in three genes (cg06418238 in RPTOR, cg00736299 in MGRN1 and cg27466532 in RAPSN), which showed significant hypomethylation in BC patients compared to healthy controls in the discovery cohort (p < 1.00 x 10-6) were selected and successfully validated in three independent cohorts (validation I, n =211; validation II, n=378; validation III, n=520). The observed methylation differences are likely not cell-type specific, as the differences were only seen in whole blood, but not in specific sub cell-types of leucocytes. Moreover, we observed in quartile analysis that women in the lower methylation quartiles of these three loci had higher ORs than women in the higher quartiles. The combined AUC of three loci was 0.79 (95%CI 0.73-0.85) in validation cohort I, and was 0.60 (95%CI 0.54-0.66) and 0.62 (95%CI 0.57-0.67) in validation cohort II and III, respectively. Our study suggests that hypomethylation of CpG sites in RPTOR, MGRN1 and RAPSN in blood is associated with BC and might serve as blood-based marker supplements for BC if these could be verified in prospective studies.
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  • 文章类型: Journal Article
    Mahogunin RING Finger 1 (MGRN1) is a ubiquitin E3 ligase known to affect spindle tilt in mitotic cells by regulating α-tubulin ubiquitination and polymerization. In cell culture systems we have found that expressing truncated mutants of MGRN1 leads to various other mitotic anomalies, such as lateral and angular spindle displacements. This seems to be independent of the MGRN1 ligase activity. Our experiments suggest that MGRN1 regulates the balance between the lower molecular weight monomeric Gαi and larger trimeric G-protein complex, along with its abundance in the ternary complex that regulates spindle positioning. The cytosolic isoforms of MGRN1 lead to the enrichment of monomeric Gαi in the cytosol and its subsequent recruitment at the plasma membrane. Excess Gαi at the cell cortex results in an imbalance in the assembly of the ternary complex regulating spindle positioning during mitosis. These observations seem independent of the ligase activity of MGRN1, although we cannot exclude the involvement of an intermediate player that acts as a substrate for MGRN1, and in turn, regulates Gαi.
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  • 文章类型: Journal Article
    Cellular quality control provides an efficient surveillance system to regulate mitochondrial turnover. This study elucidates a new interaction between the cytosolic E3 ligase mahogunin RING finger 1 (MGRN1) and the endoplasmic reticulum (ER) ubiquitin E3 ligase GP78 (also known as AMFR). Loss of Mgrn1 function has been implicated in late-onset spongiform neurodegeneration and congenital heart defects, among several developmental defects. Here, we show that MGRN1 ubiquitylates GP78 in trans through non-canonical K11 linkages. This helps maintain constitutively low levels of GP78 in healthy cells, in turn downregulating mitophagy. GP78, however, does not regulate MGRN1. When mitochondria are stressed, cytosolic Ca(2+) increases. This leads to a reduced interaction between MGRN1 and GP78 and its compromised ubiquitylation. Chelating Ca(2+) restores association between the two ligases and the in trans ubiquitylation. Catalytic inactivation of MGRN1 results in elevated levels of GP78 and a consequential increase in the initiation of mitophagy. This is important because functional depletion of MGRN1 by the membrane-associated disease-causing prion protein (Ctm)PrP affects polyubiquitylation and degradation of GP78, also leading to an increase in mitophagy events. This suggests that MGRN1 participates in mitochondrial quality control and could contribute to neurodegeneration in a subset of (Ctm)PrP-mediated prion diseases.
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