The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Liang Cui - One of the best experts on this subject based on the ideXlab platform.
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MEIS1 inhibits clear cell renal cell carcinoma cells proliferation and in vitro invasion or migration
BMC Cancer, 2017Co-Authors: Jie Zhu, Liang Cui, Xiaotao Yin, Jiangping GaoAbstract:Myeloid ecotropic viral integration site 1 (MEIS1) protein plays a synergistic causative role in acute myeloid leukemia (AML). However, MEIS1 has also shown to be a potential tumor suppressor in some other cancers, such as non-small-cell lung cancer (NSCLC) and prostate cancer. Although multiple roles of MEIS1 in cancer development and progression have been identified, there is an urgent demand to discover more functions of this molecule for further therapeutic design. MEIS1 was overexpressed via adenovirus vector in clear cell renal cell carcinoma (ccRCC) cells. Western blot and real-time qPCR (quantitative Polymerase Chain Reaction) was performed to examine the protein and mRNA levels of MEIS1. Cell proliferation, survival, in vitro migration and invasion were tested by MTT, colony formation, soft-agar, transwell (in vitro invasion/migration) assays, and tumor in vivo growthwas measured on nude mice model. In addition, flow-cytometry analysis was used to detect cell cycle arrest or non-apoptotic cell death of ccRCC cells induced by MEIS1. MEIS1 exhibits a decreased expression in ccRCC cell lines than that in non-tumor cell lines. MEIS1 overexpression inhibits ccRCC cells proliferation and induces G1/S arrest concomitant with marked reduction of G1/S transition regulators, Cyclin D1 and Cyclin A. Moreover, MEIS1-1 overexpression also induces non-apoptotic cell death of ccRCC cells via decreasing the levels of pro-survival regulators Survivin and BCL-2. Transwell migration assay (TMA) shows that MEIS1 attenuates in vitro invasion and migration of ccRCC cells with down-regulated epithelial-mesenchymal transition (EMT) process. Further, in nude mice model, MEIS1 inhibits the in vivo growth of Caki-1 cells. By investigating the role of MEIS1 in ccRCC cells’ survival, proliferation, anchorage-independent growth, cell cycle progress, apoptosis and metastasis, in the present work, we propose that MEIS1 may play an important role in clear cell renal cell carcinoma (ccRCC) development.
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MEIS1 functions as a potential ar negative regulator
Experimental Cell Research, 2014Co-Authors: Liang Cui, Fan Feng, Yutao Yang, Xingyi Hang, Jiajun Cui, Jiangping GaoAbstract:The androgen receptor (AR) plays critical roles in human prostate carcinoma progression and transformation. However, the activation of AR is regulated by co-regulators. MEIS1 protein, the homeodomain transcription factor, exhibited a decreased level in poor-prognosis prostate tumors. In this study, we investigated a potential interaction between MEIS1 and AR. We found that overexpression of MEIS1 inhibited the AR transcriptional activity and reduced the expression of AR target gene. A potential protein-protein interaction between AR and MEIS1 was identified by the immunoprecipitation and GST pull-down assays. Furthermore, MEIS1 modulated AR cytoplasm/nucleus translocation and the recruitment to androgen response element in prostate specific antigen (PSA) gene promoter sequences. In addition, MEIS1 promoted the recruitment of NCoR and SMRT in the presence of R1881. Finally, MEIS1 inhibited the proliferation and anchor-independent growth of LNCaP cells. Taken together, our data suggests that MEIS1 functions as a novel AR co-repressor.
Jiangping Gao - One of the best experts on this subject based on the ideXlab platform.
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MEIS1 inhibits clear cell renal cell carcinoma cells proliferation and in vitro invasion or migration
BMC Cancer, 2017Co-Authors: Jie Zhu, Liang Cui, Xiaotao Yin, Jiangping GaoAbstract:Myeloid ecotropic viral integration site 1 (MEIS1) protein plays a synergistic causative role in acute myeloid leukemia (AML). However, MEIS1 has also shown to be a potential tumor suppressor in some other cancers, such as non-small-cell lung cancer (NSCLC) and prostate cancer. Although multiple roles of MEIS1 in cancer development and progression have been identified, there is an urgent demand to discover more functions of this molecule for further therapeutic design. MEIS1 was overexpressed via adenovirus vector in clear cell renal cell carcinoma (ccRCC) cells. Western blot and real-time qPCR (quantitative Polymerase Chain Reaction) was performed to examine the protein and mRNA levels of MEIS1. Cell proliferation, survival, in vitro migration and invasion were tested by MTT, colony formation, soft-agar, transwell (in vitro invasion/migration) assays, and tumor in vivo growthwas measured on nude mice model. In addition, flow-cytometry analysis was used to detect cell cycle arrest or non-apoptotic cell death of ccRCC cells induced by MEIS1. MEIS1 exhibits a decreased expression in ccRCC cell lines than that in non-tumor cell lines. MEIS1 overexpression inhibits ccRCC cells proliferation and induces G1/S arrest concomitant with marked reduction of G1/S transition regulators, Cyclin D1 and Cyclin A. Moreover, MEIS1-1 overexpression also induces non-apoptotic cell death of ccRCC cells via decreasing the levels of pro-survival regulators Survivin and BCL-2. Transwell migration assay (TMA) shows that MEIS1 attenuates in vitro invasion and migration of ccRCC cells with down-regulated epithelial-mesenchymal transition (EMT) process. Further, in nude mice model, MEIS1 inhibits the in vivo growth of Caki-1 cells. By investigating the role of MEIS1 in ccRCC cells’ survival, proliferation, anchorage-independent growth, cell cycle progress, apoptosis and metastasis, in the present work, we propose that MEIS1 may play an important role in clear cell renal cell carcinoma (ccRCC) development.
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MEIS1 functions as a potential ar negative regulator
Experimental Cell Research, 2014Co-Authors: Liang Cui, Fan Feng, Yutao Yang, Xingyi Hang, Jiajun Cui, Jiangping GaoAbstract:The androgen receptor (AR) plays critical roles in human prostate carcinoma progression and transformation. However, the activation of AR is regulated by co-regulators. MEIS1 protein, the homeodomain transcription factor, exhibited a decreased level in poor-prognosis prostate tumors. In this study, we investigated a potential interaction between MEIS1 and AR. We found that overexpression of MEIS1 inhibited the AR transcriptional activity and reduced the expression of AR target gene. A potential protein-protein interaction between AR and MEIS1 was identified by the immunoprecipitation and GST pull-down assays. Furthermore, MEIS1 modulated AR cytoplasm/nucleus translocation and the recruitment to androgen response element in prostate specific antigen (PSA) gene promoter sequences. In addition, MEIS1 promoted the recruitment of NCoR and SMRT in the presence of R1881. Finally, MEIS1 inhibited the proliferation and anchor-independent growth of LNCaP cells. Taken together, our data suggests that MEIS1 functions as a novel AR co-repressor.
Patrick A Dion - One of the best experts on this subject based on the ideXlab platform.
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MEIS1 and restless legs syndrome a comprehensive review
Frontiers in Neurology, 2019Co-Authors: Faezeh Sarayloo, Patrick A Dion, Guy A RouleauAbstract:Restless legs syndrome (RLS) is a common sleep-related disorder for which the underlying biological pathways and genetic determinants are not well understood. The genetic factors so far identified explain less than 10% of the disease heritability. The first successful genome-wide association study (GWAS) of RLS was reported in 2007. This study identified multiple RLS associated risk variants including some within the non-coding regions of MEIS1. The MEIS1 GWAS signals are some of the strongest genetic associations reported for any common disease. MEIS1 belongs to the homeobox containing transcriptional regulatory network (HOX). Work in C. elegans showed a link between the MEIS1 ortholog and iron homeostasis, which is in line with the fact that central nervous system (CNS) iron insufficiency is thought to be a cause of RLS. Zebrafish and mice have been used to study the MEIS1 gene identifying an RLS-associated-SNP dependent enhancer activity from the highly conserved non-coding regions (HCNR) of MEIS1. Furthermore, this gene shows a lower expression of mRNA and protein in blood and thalamus of individuals with the MEIS1 RLS risk haplotype. Simulating this reduced MEIS1 expression in mouse models resulted in circadian hyperactivity, a phenotype compatible with RLS. While MEIS1 shows a strong association with RLS, the protein's function that is directly linked to an RLS biological pathway remains to be discovered. The links to iron and the enhancer activity of the HCNRs of MEIS1 suggest promising links to RLS pathways, however more in-depth studies on this gene's function are required. One important aspect of MEIS1's role in RLS is the fact that it encodes a homeobox containing transcription factor, which is essential during development. Future studies with more focus on the transcriptional regulatory role of MEIS1 may open novel venues for RLS research.
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restless legs syndrome associated MEIS1 risk variant influences iron homeostasis
Annals of Neurology, 2011Co-Authors: Helene Catoire, Patrick A Dion, Lan Xiong, Mourabit Amari, Rebecca Gaudet, Simon L Girard, Anne Noreau, Claudia Gaspar, Gustavo Turecki, Jacques MontplaisirAbstract:Restless legs syndrome (RLS) is a frequent sleep disorder that is linked to disturbed iron homeostasis. Genetic studies identified MEIS1 as an RLS-predisposing gene, where the RLS risk haplotype is associated with decreased MEIS1 mRNA and protein expression. We show here that RNA interference treatment of the MEIS1 worm orthologue increases ferritin expression in Caenorhabditis elegans and that the RLS-associated haplotype leads to increased expression of ferritin and DMT1 in RLS brain tissues. Additionally, human cells cultured under iron-deficient conditions show reduced MEIS1 expression. Our data establish a link between the RLS MEIS1 gene and iron metabolism.
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MEIS1 intronic risk haplotype associated with restless legs syndrome affects its mrna and protein expression levels
Human Molecular Genetics, 2009Co-Authors: Lan Xiong, Patrick A Dion, Helene Catoire, Simon L Girard, Claudia Gaspar, Ronald G Lafreniere, Anastasia Levchenko, Jean Baptiste Riviere, Laura M Fiori, Judith StongeAbstract:Restless legs syndrome (RLS) is a common neurological disorder characterized by an irresistible urge to move the legs at night, which is often accompanied by unpleasant sensations. A recent genomewide association study identified an association between RLS and intronic markers from the MEIS1 gene. Comparative genomic analysis indicates that MEIS1 is the only gene encompassed in this evolutionarily conserved chromosomal segment, i.e. a conservation synteny block, from mammals to fish. We carried out a series of experiments to delineate the role of MEIS1 in RLS pathogenesis and the underlying genetic mechanism. We sequenced all 13 MEIS1 exons and their splice junctions in 285 RLS probands with confirmed clinical diagnosis and did not identify any causative coding or exon-intron junction mutations. We found no evidence of structural variation or disease-associated haplotype differential splicing. However, sequencing of conserved regions of MEIS1 introns 8 and 9 identified a novel single nucleotide polymorphism (C13B_2) significantly associated with RLS (allelic association, P = 1.81E-07). We detected a significant decrease in MEIS1 mRNA expression by quantitative real-time polymerase chain reaction in lymphoblastoid cell lines (LCLs) and brain tissues from RLS patients homozygous for the intronic RLS risk haplotype, compared with those homozygous for the non-risk haplotype. Finally, we found significantly decreased MEIS1 protein levels in the same batch of LCLs and brain tissues from the homozygous carriers of the risk haplotype, compared with the homozygous non-carriers. Therefore, these data suggest that reduced expression of the MEIS1 gene, possibly through intronic cis-regulatory element(s), predisposes to RLS.
Miguel Torres - One of the best experts on this subject based on the ideXlab platform.
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investigation of dopaminergic signalling in meis homeobox 1 MEIS1 deficient mice as an animal model of restless legs syndrome
Journal of Sleep Research, 2021Co-Authors: Lucile Cathiard, Miguel Torres, Valerie Fraulob, Daniel D Lam, Juliane Winkelmann, Wojciech KrezelAbstract:Restless legs syndrome (RLS) is a common neurological disorder in which sensorimotor symptoms lead to sleep disturbances with substantial impact on life quality. RLS is caused by a combination of genetic and environmental factors, and Meis homeobox 1 (MEIS1) was identified as the main genetic risk factor. The efficacy of dopaminergic agonists, including dopamine D2 receptor (DRD2) agonists, for treating RLS led to the hypothesis of dopaminergic impairment. However, it remains unclear whether it is directly involved in the disease aetiology and what the role of MEIS1 is considering its developmental and postnatal expression in the striatum, a critical structure in motor control. We addressed the role of MEIS1 in striatal dopaminergic signalling in MEIS1+/- mice, a valid animal model of RLS, and in MEIS1Drd2 -/- mice carrying a somatic null mutation of MEIS1 in Drd2+ neurones. Motor behaviours, pharmacological exploration of DRD2 signalling, and quantitative analyses of DRD2+ and DRD1+ expressing neurones were investigated. Although MEIS1+/- mice displayed an RLS-like phenotype, including motor hyperactivity at the beginning of the rest phase, no reduction of dopaminoceptive neurones was observed in the striatum. Moreover, the null mutation of MEIS1 in DRD2+ cells did not lead to RLS-like symptoms and dysfunction of the DRD2 pathway. These data indicate that MEIS1 does not modulate DRD2-dependent signalling in a cell-autonomous manner. Thus, the efficiency of D2 -like agonists may reflect the involvement of other dopaminergic receptors or normalisation of motor circuit abnormalities downstream from defects caused by MEIS1 dysfunction.
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sleep disturbance by pramipexole is modified by MEIS1 in mice
Journal of Sleep Research, 2018Co-Authors: Aaro V. Salminen, Barbara Schormair, Miguel Torres, Cornelia Flachskamm, Bertram Mullermyhsok, Mayumi Kimura, Juliane WinkelmannAbstract:Meis homeobox 1 (MEIS1) is a transcription factor functioning in the development of the nervous system and the cardiovascular system. Both common and rare variants within the gene have been associated with restless legs syndrome (RLS), while its association with symptoms of insomnia has also been discovered recently. RLS is associated with sleep disturbances, and while MEIS1 haploinsufficiency is one of the most promising strategies for an RLS animal model, sleep phenotyping of MEIS1 knockout mice has never been conducted. We report a detailed sleep analysis of heterozygous MEIS1 knockout mice and challenge it with pramipexole, a dopamine agonist used in the treatment of RLS. At baseline, the MEIS1-haploinsufficient mice had a trend towards lower delta power in the electroencephalogram (EEG) during sleep compared to the wild-type littermates, possibly indicating reduced sleep quality, but not sleep fragmentation. Pramipexole had a sleep disrupting effect in both genotype groups. In addition, it exerted differential effects on the EEG power spectra of the two mouse lines, remarkably elevating the theta power of the mutant mice during recovery more than that of the wild-types. In conclusion, MEIS1 haploinsufficiency seems to have only a modest effect on sleep, but the gene may interact with the sleep-disrupting effect of dopamine agonists.
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ectopic MEIS1 expression in the mouse limb bud alters p d patterning in a pbx1 independent manner
The International Journal of Developmental Biology, 2009Co-Authors: Nadia Mercader, Licia Selleri, Luis M Criado, Pilar Pallares, Carlos Parras, Michael L Cleary, Miguel TorresAbstract:During limb development, expression of the TALE homeobox transcription factor MEIS1 is activated by retinoic acid in the proximal-most limb bud regions, which give rise to the upper forelimb and hindlimb. Early subdivision of the limb bud into proximal Meis-positive and distal Meis-negative domains is necessary for correct proximo-distal (P-D) limb development in the chick, since ectopic MEIS1 overexpression abolishes distal limb structures, produces a proximal shift of limb identities along the P-D axis, and proximalizes distal limb cell affinity properties. To determine whether Meis activity is also required for P-D limb specification in mammals, we generated transgenic mice ectopically expressing MEIS1 in the distal limb mesenchyme under the control of the Msx2 promoter. Msx2:MEIS1 transgenic mice display altered P-D patterning and shifted P-D Hox gene expression domains, similar to those previously described for the chicken. Meis proteins function in cooperation with PBX factors, another TALE homeodomain subfamily. Meis-Pbx interaction is required for nuclear localization of both proteins in cell culture, and is important for their DNA-binding and transactivation efficiency. During limb development, Pbx1 nuclear expression correlates with the Meis expression domain, and Pbx1 has been proposed as the main Meis partner in this context; however, we found that Pbx1 deficiency did not modify the limb phenotype of Msx2:MEIS1 mice. Our results indicate a conserved role of Meis activity in P-D specification of the tetrapod limb and suggest that Pbx function in this context is either not required or is provided by partners other than Pbx1.
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the homeodomain protein MEIS1 is essential for definitive hematopoiesis and vascular patterning in the mouse embryo
Developmental Biology, 2005Co-Authors: Valeria Azcoitia, Carlos Martineza, Miguel Aracil, Miguel TorresAbstract:Homeodomain proteins of the Meis subfamily are expressed dynamically in several organs during embryogenesis and exert potent regulatory activity through their interaction with Hox proteins and other transcription factors. Here we show that MEIS1 is expressed in the hematopoietic stem cell (HSC) compartment in the fetal liver, and in the primary sites of definitive hematopoiesis, including the aorta-gonad-mesonephros (AGM) mesenchyme, the hemogenic embryonic arterial endothelium, and hematopoietic clusters within the aorta, vitelline, and umbilical arteries. We inactivated the MEIS1 gene in mice and found that MEIS1 mutant mice die between embryonic days 11.5 and 14.5, showing internal hemorrhage, liver hypoplasia, and anemia. In MEIS1 mutant mouse fetal liver and AGM, HSC compartments are severely underdeveloped and colony-forming potential is profoundly impaired. AGM mesenchymal cells expressing Runx1, an essential factor for definitive HSC specification, are almost absent in mutant mice. In addition, hematopoietic clusters in the dorsal aorta, vitelline, and umbilical arteries are reduced in size and number. These results show a requirement for MEIS1 in the establishment of definitive hematopoiesis in the mouse embryo. MEIS1 mutant mice also displayed complete agenesis of the megakaryocyte lineage and localized defects in vascular patterning, which may cause the hemorrhagic phenotype.
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opposing ra and fgf signals control proximodistal vertebrate limb development through regulation of meis genes
Development, 2000Co-Authors: Nadia Mercader, Esther Leonardo, Maria Elisa Piedra, Carlos Martineza, Miguel TorresAbstract:Vertebrate limbs develop in a temporal proximodistal sequence, with proximal regions specified and generated earlier than distal ones. Whereas considerable information is available on the mechanisms promoting limb growth, those involved in determining the proximodistal identity of limb parts remain largely unknown. We show here that retinoic acid (RA) is an upstream activator of the proximal determinant genes MEIS1 and Meis2. RA promotes proximalization of limb cells and endogenous RA signaling is required to maintain the proximal Meis domain in the limb. RA synthesis and signaling range, which initially span the entire lateral plate mesoderm, become restricted to proximal limb domains by the apical ectodermal ridge (AER) activity following limb initiation. We identify fibroblast growth factor (FGF) as the main molecule responsible for this AER activity and propose a model integrating the role of FGF in limb cell proliferation, with a specific function in promoting distalization through inhibition of RA production and signaling.
Guy A Rouleau - One of the best experts on this subject based on the ideXlab platform.
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MEIS1 and restless legs syndrome a comprehensive review
Frontiers in Neurology, 2019Co-Authors: Faezeh Sarayloo, Patrick A Dion, Guy A RouleauAbstract:Restless legs syndrome (RLS) is a common sleep-related disorder for which the underlying biological pathways and genetic determinants are not well understood. The genetic factors so far identified explain less than 10% of the disease heritability. The first successful genome-wide association study (GWAS) of RLS was reported in 2007. This study identified multiple RLS associated risk variants including some within the non-coding regions of MEIS1. The MEIS1 GWAS signals are some of the strongest genetic associations reported for any common disease. MEIS1 belongs to the homeobox containing transcriptional regulatory network (HOX). Work in C. elegans showed a link between the MEIS1 ortholog and iron homeostasis, which is in line with the fact that central nervous system (CNS) iron insufficiency is thought to be a cause of RLS. Zebrafish and mice have been used to study the MEIS1 gene identifying an RLS-associated-SNP dependent enhancer activity from the highly conserved non-coding regions (HCNR) of MEIS1. Furthermore, this gene shows a lower expression of mRNA and protein in blood and thalamus of individuals with the MEIS1 RLS risk haplotype. Simulating this reduced MEIS1 expression in mouse models resulted in circadian hyperactivity, a phenotype compatible with RLS. While MEIS1 shows a strong association with RLS, the protein's function that is directly linked to an RLS biological pathway remains to be discovered. The links to iron and the enhancer activity of the HCNRs of MEIS1 suggest promising links to RLS pathways, however more in-depth studies on this gene's function are required. One important aspect of MEIS1's role in RLS is the fact that it encodes a homeobox containing transcription factor, which is essential during development. Future studies with more focus on the transcriptional regulatory role of MEIS1 may open novel venues for RLS research.