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Peter Koopman - One of the best experts on this subject based on the ideXlab platform.
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Genetic ablation of SOX18 function suppresses tumor lymphangiogenesis and metastasis of melanoma in mice
Cancer research, 2012Co-Authors: Tam Duong, Peter Koopman, Steven T. Proulx, Paola Luciani, Jean-christophe Leroux, Michael Detmar, Mathias FrancoisAbstract:The lymphatic vasculature provides a major route for tumor metastasis and inhibiting neolymphangiogenesis induced by tumors can reduce metastasis in animal models. Developmental biology studies have identified the transcription factor SOX18 as a critical switch for lymphangiogenesis in the mouse embryo. Here, we show that SOX18 is also critical for tumor-induced lymphangiogenesis, and we show that suppressing SOX18 function is sufficient to impede tumor metastasis. Immunofluorescence analysis of murine tumor xenografts showed that SOX18 is reexpressed during tumor-induced neolymphangiogenesis. Tumors generated by implantation of firefly luciferase-expressing B16-F10 melanoma cells exhibited a reduced rate of metastasis to the regional draining lymph node in SOX18-deficient mice, as assessed by live bioluminescence imaging. Lower metastatic rates correlated with reduced tumoral lymphatic vessel density and diameter and with impaired drainage of peritumoral injected liposomes specific for lymph vessels from the sentinel lymph nodes. Overall, our findings suggested that SOX18 induction is a key step in mediating tumor lymphangiogenesis and metastasis, and they identify SOX18 as a potential therapeutic target for metastatic blockade.
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SOX18 and Sox7 play redundant roles in vascular development
Blood, 2007Co-Authors: Solei Cermenati, Peter Koopman, Elisabetta Dejana, Silvia Moleri, Franco Cotelli, Simona Cimbro, Paola Corti, Luca Del Giacco, Roberta Amodeo, Monica BeltrameAbstract:Mutations in SOX18 cause the human hypotrichosis-lymphedema-telangiectasia (HLT) syndrome. Their murine counterparts are the spontaneous ragged mutants, showing combined defects in hair follicle, blood vessel, and lymphatic vessel development. Mice null for SOX18 display only mild coat defects, suggesting a dominant-negative effect of SOX18/ragged mutations and functional redundancy between SOX18 and other Sox-F proteins. We addressed this point in zebrafish. The zebrafish homologs of SOX18 and of Sox7 are expressed in angioblasts and in the endothelial component of nascent blood vessels in embryos. Knockdown of either gene, using moderate doses of specific morpholinos, had minimal effects on vessels. In contrast, simultaneous knockdown of both genes resulted in multiple fusions between the major axial vessels. With combined use of transgenic lines and molecular markers, we could show that endothelial cells are specified, but fail to acquire a correct arteriovenous identity. Venous endothelial cell differentiation was more severely affected than arterial. Thus, sox7 and SOX18 play redundant but collectively essential roles in the establishment of proper arteriovenous identity in zebrafish. Our data suggest that a defect in arteriovenous identity could be responsible for the formation of telangiectases in patients with HLT.
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Redundant roles of Sox17 and SOX18 in early cardiovascular development of mouse embryos
Biochemical and Biophysical Research Communications, 2007Co-Authors: Youhei Sakamoto, Yutaroh Miura, Yukio Saijoh, Kenshiro Hara, Peter Koopman, Naoki Tsunekawa, Masamichi Kurohmaru, Masami Kanai-azuma, Toshiyasu Matsui, Yoshiakira KanaiAbstract:Sox7, -17 and -18 constitute the Sox subgroup F (SoxF) of HMG box transcription factor genes, which all are co-expressed in developing vascular endothelial cells in mice. Here we characterized cardiovascular phenotypes of Sox17/SOX18-double and Sox17-single null embryos during early-somite stages. Whole-mount PECAM staining demonstrated the aberrant heart looping, enlarged cardinal vein and mild defects in anterior dorsal aorta formation in Sox17 single-null embryos. The Sox17/SOX18 double-null embryos showed more severe defects in formation of anterior dorsal aorta and head/cervical microvasculature, and in some cases, aberrant differentiation of endocardial cells and defective fusion of the endocardial tube. However, the posterior dorsal aorta and allantoic microvasculature was properly formed in all of the Sox17/SOX18 double-null embryos. The anomalies in both anterior dorsal aorta and head/cervical vasculature corresponded with the weak Sox7 expression sites. This suggests the region-specific redundant activities of three SoxF members along the anteroposterior axis of embryonic vascular network.
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Redundant roles of Sox17 and SOX18 in postnatal angiogenesis in mice
Journal of Cell Science, 2006Co-Authors: Toshiyasu Matsui, Kenshiro Hara, Peter Koopman, Masamichi Kurohmaru, Masami Kanai-azuma, Shogo Matoba, Ryuji Hiramatsu, Hayato Kawakami, Yoshiakira KanaiAbstract:Sox7, Sox17 and SOX18 constitute group F of the Sox family of HMG box transcription factor genes. Dominant-negative mutations in SOX18 underlie the cardiovascular defects observed in ragged mutant mice. By contrast, SOX18(-/-) mice are viable and fertile, and display no appreciable anomaly in their vasculature, suggesting functional compensation by the two other SoxF genes. Here, we provide direct evidence for redundant function of Sox17 and SOX18 in postnatal neovascularization by generating Sox17(+/-) -SOX18(-/-) double mutant mice. Whereas SOX18(-/-) and Sox17(+/-) -SOX18(+/-) mice showed no vascular defects, approximately half of the Sox17(+/-) -SOX18(-/-) pups died before postnatal day 21 (P21). They showed reduced neovascularization in the liver sinusoids and kidney outer medulla vasa recta at P7, which most likely caused the ischemic necrosis observed by P14 in hepatocytes and renal tubular epithelia. Those that survived to adulthood showed similar, but milder, vascular anomalies in both liver and kidney, and females were infertile with varying degrees of vascular abnormalities in the reproductive organs. These anomalies corresponded with sites of expression of Sox7 and Sox17 in the developing postnatal vasculature. In vitro angiogenesis assays, using primary endothelial cells isolated from the P7 livers, showed that the Sox17(+/-) -SOX18(-/-) endothelial cells were defective in endothelial sprouting and remodeling of the vasculature in a phenotype-dependent manner. Therefore, our findings indicate that Sox17 and SOX18, and possibly all three SoxF genes, are cooperatively involved in mammalian vascular development.
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Effect of Disrupted SOX18 Transcription Factor Function on Tumor Growth, Vascularization, and Endothelial Development
Journal of the National Cancer Institute, 2006Co-Authors: Neville Young, Dagmar Wilhelm, Jane E. Olsson, George E.o. Muscat, Christopher N. Hahn, Alisa M Poh, Carolyn Dong, Peter G. Parsons, Jennifer R. Gamble, Peter KoopmanAbstract:Background. The growth of solid tumors depends on establishing blood supply; thus, inhibiting tumor angiogenesis has been a long-term goal in cancer therapy. The SOX18 transcription factor is a key regulator of murine and human blood vessel formation. Methods: We established allograft melanoma tumors in wild-type mice, SOX18-null mice, and mice expressing a dominant-negative form of SOX18 (SOX18RaOp) (n = 4 per group) and measured tumor growth and microvessel density by immunohistochemical analysis with antibodies to the endothelial marker CD31 and the pericyte marker NG2. We also assessed the affects of disrupted SOX18 function on MCF-7 human breast cancer and human umbilical vein endothelial cell (HUVEC) proliferation by measuring BrdU incorporation and by MTS assay, cell migration using Boyden chamber assay, and capillary tube formation in vitro. All statistical tests were two-sided. Results: Allograft tumors in SOX18-null and SOX18RaOp mice grew more slowly than those in wild-type mice (tumor volume at day 14, SOX18 null, mean = 486 mm(3), 95% confidence interval [CI] = 345 mm(3) to 627 mm(3), p = .004; SOX18RaOp, mean = 233 mm(3), 95% CI = 73 mm(3) to 119 mm(3), p < .001; versus wild-type, mean = 817 mm(3), 95% CI = 643 mm(3) to 1001 mm(3)) and had fewer CD31- and NG2-expressing vessels. Expression of dominant-negative SOX18 reduced the proliferation of MCF-7 cells (BrdU incorporation: MCF-7(Ra) = 20%, 95% CI = 15% to 25% versus MCF-7 = 41%, 95% CI = 35% to 45%; P = .013) and HUVECs (optical density at 490 nm, empty vector, mean = 0.46 versus SOX18 mean = 0.29; difference = 0.17, 95% CI = 0.14 to 0.19; P = .001) compared with control subjects. Overexpression of wild-type SOX18 promoted capillary tube formation of HUVECs in vitro, whereas expression of dominant-negative SOX18 impaired tube formation of HUVECs and the migration of MCF-7 cells via the disruption of the actin cytoskeleton. Conclusions: SOX18 is a potential target for antiangiogenic therapy of human cancers.
Mathias Francois - One of the best experts on this subject based on the ideXlab platform.
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dominant negative SOX18 function inhibits dermal papilla maturation and differentiation in all murine hair types
Development, 2017Co-Authors: Reha Villani, Samantha Hodgso, Julie M D Legrand, Jessica Greaney, Ho Yi Wong, Cathy Picholthievend, Christelle Adolphe, Ando Wainwigh, Mathias Francois, Kiarash KhosrotehraniAbstract:SOX family proteins SOX2 and SOX18 have been reported as being essential in determining hair follicle type; however, the role they play during development remains unclear. Here, we demonstrate that SOX18 regulates the normal differentiation of the dermal papilla of all hair types. In guard (primary) hair dermal condensate (DC) cells, we identified transient SOX18 in addition to SOX2 expression at E14.5, which allowed fate tracing of primary DC cells until birth. Similarly, expression of SOX18 was detected in the DC cells of secondary hairs at E16.5 and in tertiary hair at E18.5. Dominant-negative SOX18 mutation (opposum) did not prevent DC formation in any hair type. However, it affected dermal papilla differentiation, restricting hair formation especially in secondary and tertiary hairs. This SOX18 mutation also prevented neonatal dermal cells or dermal papilla spheres from inducing hair in regeneration assays. Microarray expression studies identified WNT5A and TNC as potential downstream effectors of SOX18 that are important for epidermal WNT signalling. In conclusion, SOX18 acts as a mesenchymal molecular switch necessary for the formation and function of the dermal papilla in all hair types.
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structure and decoy mediated inhibition of the SOX18 prox1 dna interaction
Nucleic Acids Research, 2016Co-Authors: Miriam Klaus, Nina Prokoph, Mathias Girbig, X.m. Wang, Yong-heng Huang, Yogesh Srivastava, Linlin Hou, Kamesh Narasimhan, Prasanna R. Kolatkar, Mathias FrancoisAbstract:The transcription factor (TF) SOX18 drives lymphatic vessel development in both embryogenesis and tumour-induced neo-lymphangiogenesis. Genetic disruption of SOX18 in a mouse model protects from tumour metastasis and established the SOX18 protein as a molecular target. Here, we report the crystal structure of the SOX18 DNA binding high-mobility group (HMG) box bound to a DNA element regulating Prox1 transcription. The crystals diffracted to 1.75A presenting the highest resolution structure of a SOX/DNA complex presently available revealing water structure, structural adjustments at the DNA contact interface and non-canonical conformations of the DNA backbone. To explore alternatives to challenging small molecule approaches for targeting the DNA-binding activity of SOX18, we designed a set of five decoys based on modified Prox1-DNA. Four decoys potently inhibited DNA binding of SOX18 in vitro and did not interact with non-SOX TFs. Serum stability, nuclease resistance and thermal denaturation assays demonstrated that a decoy circularized with a hexaethylene glycol linker and terminal phosphorothioate modifications is most stable. This SOX decoy also interfered with the expression of a luciferase reporter under control of a SOX18-dependent VCAM1 promoter in COS7 cells. Collectively, we propose SOX decoys as potential strategy for inhibiting SOX18 activity to disrupt tumour-induced neo-lymphangiogenesis.
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Structure and decoy-mediated inhibition of the SOX18/Prox1-DNA interaction
Nucleic acids research, 2016Co-Authors: Miriam Klaus, Nina Prokoph, Mathias Girbig, X.m. Wang, Yong-heng Huang, Yogesh Srivastava, Linlin Hou, Kamesh Narasimhan, Prasanna R. Kolatkar, Mathias FrancoisAbstract:The transcription factor (TF) SOX18 drives lymphatic vessel development in both embryogenesis and tumour-induced neo-lymphangiogenesis. Genetic disruption of SOX18 in a mouse model protects from tumour metastasis and established the SOX18 protein as a molecular target. Here, we report the crystal structure of the SOX18 DNA binding high-mobility group (HMG) box bound to a DNA element regulating Prox1 transcription. The crystals diffracted to 1.75A presenting the highest resolution structure of a SOX/DNA complex presently available revealing water structure, structural adjustments at the DNA contact interface and non-canonical conformations of the DNA backbone. To explore alternatives to challenging small molecule approaches for targeting the DNA-binding activity of SOX18, we designed a set of five decoys based on modified Prox1-DNA. Four decoys potently inhibited DNA binding of SOX18 in vitro and did not interact with non-SOX TFs. Serum stability, nuclease resistance and thermal denaturation assays demonstrated that a decoy circularized with a hexaethylene glycol linker and terminal phosphorothioate modifications is most stable. This SOX decoy also interfered with the expression of a luciferase reporter under control of a SOX18-dependent VCAM1 promoter in COS7 cells. Collectively, we propose SOX decoys as potential strategy for inhibiting SOX18 activity to disrupt tumour-induced neo-lymphangiogenesis.
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SOX18 Genetically Interacts With VegfC to Regulate Lymphangiogenesis in Zebrafish
Arteriosclerosis thrombosis and vascular biology, 2013Co-Authors: Solei Cermenati, Silvia Moleri, Christine Neyt, Erica Bresciani, Silvia Carra, Daniela R. Grassini, Alice Omini, Michela Goi, Franco Cotelli, Mathias FrancoisAbstract:Objective— Lymphangiogenesis is regulated by transcription factors and by growth factor pathways, but their interplay has not been extensively studied so far. We addressed this issue in zebrafish. Approach and Results— Mutations in the transcription factor–coding gene SOX18 and in VEGFR3 cause lymphedema, and the VEGFR3/Flt4 ligand VEGFC plays an evolutionarily conserved role in lymphangiogenesis. Here, we report a strong genetic interaction between SOX18 and VegfC in the early phases of lymphatic development in zebrafish. Knockdown of SOX18 selectively impaired lymphatic sprouting from the cardinal vein and resulted in defective lymphatic thoracic duct formation. SOX18 and the related protein Sox7 play redundant roles in arteriovenous differentiation. We used a novel transgenic line that enables inducible expression of a dominant-negative mutant form of mouse SOX18 protein. Our data led us to conclude that SOX18 is crucially involved in lymphangiogenesis after arteriovenous differentiation. Combined partial knockdown of SOX18 and vegfc , using subcritical doses of specific morpholinos, revealed a synergistic interaction in both venous and lymphatic sprouting from the cardinal vein and greatly impaired thoracic duct formation. Conclusions— This interaction suggests a previously unappreciated crosstalk between the growth factor and transcription factor pathways that regulate lymphangiogenesis in development and disease.
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Genetic ablation of SOX18 function suppresses tumor lymphangiogenesis and metastasis of melanoma in mice
Cancer research, 2012Co-Authors: Tam Duong, Peter Koopman, Steven T. Proulx, Paola Luciani, Jean-christophe Leroux, Michael Detmar, Mathias FrancoisAbstract:The lymphatic vasculature provides a major route for tumor metastasis and inhibiting neolymphangiogenesis induced by tumors can reduce metastasis in animal models. Developmental biology studies have identified the transcription factor SOX18 as a critical switch for lymphangiogenesis in the mouse embryo. Here, we show that SOX18 is also critical for tumor-induced lymphangiogenesis, and we show that suppressing SOX18 function is sufficient to impede tumor metastasis. Immunofluorescence analysis of murine tumor xenografts showed that SOX18 is reexpressed during tumor-induced neolymphangiogenesis. Tumors generated by implantation of firefly luciferase-expressing B16-F10 melanoma cells exhibited a reduced rate of metastasis to the regional draining lymph node in SOX18-deficient mice, as assessed by live bioluminescence imaging. Lower metastatic rates correlated with reduced tumoral lymphatic vessel density and diameter and with impaired drainage of peritumoral injected liposomes specific for lymph vessels from the sentinel lymph nodes. Overall, our findings suggested that SOX18 induction is a key step in mediating tumor lymphangiogenesis and metastasis, and they identify SOX18 as a potential therapeutic target for metastatic blockade.
Brett M. Hosking - One of the best experts on this subject based on the ideXlab platform.
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Sox7 and Sox17 are strain-specific modifiers of the lymphangiogenic defects caused by SOX18 dysfunction in mice.
Development (Cambridge England), 2009Co-Authors: Brett M. Hosking, Mathias Francois, Dagmar Wilhelm, Fabrizio Orsenigo, Andrea Caprini, Terje Svingen, D. Tutt, Tara-lynne Davidson, Catherine M. Browne, Elisabetta DejanaAbstract:Developmental defects caused by targeted gene inactivation in mice are commonly subject to strain-specific modifiers that modulate the severity of the phenotype. Although several genetic modifier loci have been mapped in mice, the gene(s) residing at these loci are mostly unidentified, and the molecular mechanisms of modifier action remain poorly understood. Mutations in SOX18 cause a variable phenotype in the human congenital syndrome hypotrichosis-lymphedema-telangiectasia, and the phenotype of SOX18-null mice varies from essentially normal to completely devoid of lymphatic vasculature and lethal, depending on the strain of the mice, suggesting a crucial role for strain-specific modifiers in this system. Here we show that two closely related Group F Sox factors, SOX7 and SOX17, are able to functionally substitute for SOX18 in vitro and in vivo. SOX7 and SOX17 are not normally expressed during lymphatic development, excluding a conventional redundancy mechanism. Instead, these genes are activated specifically in the absence of SOX18 function, and only in certain strains. Our studies identify Sox7 and Sox17 as modifiers of the SOX18 mutant phenotype, and reveal their mechanism of action as a novel mode of strain-specific compensatory upregulation.
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SOX18 induces development of the lymphatic vasculature in mice
Nature, 2008Co-Authors: Mathias Francois, Brett M. Hosking, Dagmar Wilhelm, Fabrizio Orsenigo, Andrea Caprini, Catherine M. Browne, Karri Paavonen, Tara Karnezis, Ramin Shayan, Meredith DownesAbstract:The lymphatic system plays a key role in tissue fluid regulation and tumour metastasis, and lymphatic defects underlie many pathological states including lymphoedema, lymphangiectasia, lymphangioma and lymphatic dysplasia. However, the origins of the lymphatic system in the embryo, and the mechanisms that direct growth of the network of lymphatic vessels, remain unclear. Lymphatic vessels are thought to arise from endothelial precursor cells budding from the cardinal vein under the influence of the lymphatic hallmark gene Prox1 (prospero homeobox 1; ref. 4). Defects in the transcription factor gene SOX18 (SRY (sex determining region Y) box 18) cause lymphatic dysfunction in the human syndrome hypotrichosis-lymphoedema-telangiectasia, suggesting that SOX18 may also play a role in lymphatic development or function. Here we use molecular, cellular and genetic assays in mice to show that SOX18 acts as a molecular switch to induce differentiation of lymphatic endothelial cells. SOX18 is expressed in a subset of cardinal vein cells that later co-express Prox1 and migrate to form lymphatic vessels. SOX18 directly activates Prox1 transcription by binding to its proximal promoter. Overexpression of SOX18 in blood vascular endothelial cells induces them to express Prox1 and other lymphatic endothelial markers, while SOX18-null embryos show a complete blockade of lymphatic endothelial cell differentiation from the cardinal vein. Our findings demonstrate a critical role for SOX18 in developmental lymphangiogenesis, and suggest new avenues to investigate for therapeutic management of human lymphangiopathies.
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the vcam 1 gene that encodes the vascular cell adhesion molecule is a target of the sry related high mobility group box gene SOX18
Journal of Biological Chemistry, 2004Co-Authors: Brett M. Hosking, Peter Koopman, Meredith Downes, S Mary C Wang, George E.o. MuscatAbstract:Abstract VCAM-1 (vascular cell adhesion molecule-1) and SOX18 are involved in vascular development. VCAM-1 is an important adhesion molecule that is expressed on endothelial cells and has a critical role in endothelial activation, inflammation, lymphatic pathophysiology, and atherogenesis. The Sry-related high mobility group box factor SOX18 has previously been implicated in endothelial pathologies. Mutations in human and mouse SOX18 leads to hypotrichosis and lymphedema. Furthermore, both SOX18 and VCAM-1 have very similar spatio-temporal patterns of expression, which is suggestive of cross-talk. We use biochemical techniques, cell culture systems, and the ragged opossum (RaOP) mouse model with a naturally occurring mutation in SOX18 to demonstrate that VCAM-1 is an important target of SOX18. Transfection, site-specific mutagenesis, and gel shift analyses demonstrated that SOX18 directly targeted and trans-activated VCAM-1 expression. Importantly, the naturally occurring SOX18 mutant attenuates the expression and activation of VCAM-1 in vitro. Furthermore, in vivo quantitation of VCAM-1 mRNA levels in wild type and RaOP mice demonstrates that RaOP animals show a dramatic and significant reduction in VCAM-1 mRNA expression in lung, skin, and skeletal muscle. Our observation that the VCAM-1 gene is an important target of SOX18 provides the first molecular insights into the vascular abnormalities in the mouse mutant ragged and the human hypotrichosislymphedema-telangiectasia disorder.
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SOX18 mutations in the ragged mouse alleles ragged-like and opossum.
Genesis (New York N.Y. : 2000), 2003Co-Authors: Kristy M. James, George E.o. Muscat, Brett M. Hosking, Jennifer M. Gardner, Peter KoopmanAbstract:The ragged (Ra) spontaneous mouse mutant is characterised by abnormalities in its coat and cardiovascular system. Four alleles are known and we have previously described mutations in the transcription factor gene SOX18 in the Ra and Ra(J) alleles. We report here SOX18 mutations in the remaining two ragged alleles, opossum (Ra(op)) and ragged-like (Ragl). The single-base deletions cause a C-terminal frameshift, abolishing transcriptional trans-activation and impairing interaction with the partner protein MEF2C. The nature of these mutations, together with the near-normal phenotype of SOX18-null mice, suggests that the ragged mutant SOX18 proteins act in a dominant-negative fashion. The four ragged mutants represent an allelic series that reveal SOX18 structure-function relationships and implicate related SOX proteins in cardiovascular and hair follicle development.
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SOX18 directly interacts with MEF2C in endothelial cells.
Biochemical and biophysical research communications, 2001Co-Authors: Brett M. Hosking, Peter Koopman, Sarah Penning, Sc Mary Wang, Shen Liang Chen, George E.o. MuscatAbstract:Recently, we demonstrated that mutations in the Sry-related HMG box gene SOX18 underlie vascular and hair follicle defects in the mouse allelic mutants ragged (Ra) and RaJ. Ra mice display numerous anomalies in the homozygote including, oedema, peritoneal secretions, and are almost completely naked. SOX18 and the MADS box transcription factor, Mef2C, are expressed in developing endothelial cells. Null mutants in SOX18 and Mef2c display overlapping phenotypic abnormalities, hence, we investigated the relationship between these two DNA binding proteins. We report here the direct interaction between MEF2C and SOX18 proteins, and establish that these proteins are coexpressed in vivo in endothelial cell nuclei. MEF2C expression potentiates SOX18-mediated transcription in vivo and regulates the function of the SOX18 activation domain. Interestingly, MEF2C fails to interact or co-activate transcription with the Ra or RaJ mutant SOX18 proteins. These results suggest that MEF2C and SOX18 may be important partners directing the transcriptional regulation of vascular development.
Wei Wang - One of the best experts on this subject based on the ideXlab platform.
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down regulation of SOX18 inhibits laryngeal carcinoma cell proliferation migration and invasion through jak2 stat3 signaling
Bioscience Reports, 2019Co-Authors: Qingyuan Zhang, Jie Zhou, Junyu Guo, Weina Wang, Wei WangAbstract:Laryngeal carcinoma is one of the most common malignant tumors of the head, neck, and respiratory tract. The aim of the present study is to explore the biological function of SRY-related HMG-box 18 (SOX18) in laryngeal carcinoma cells and study the molecular mechanism involved. Initial findings indicate that the expression of SOX18 was increased in laryngeal carcinoma cell lines and tissues. The effect of SOX18 on laryngeal carcinoma cell proliferation, cell cycle, apoptosis, invasion, and migration was also identified. The results indicated that down-regulation of SOX18 significantly inhibited cell proliferation, migration, and invasion, and induced cell-cycle arrest in G0/G1 phase and apoptosis of laryngeal carcinoma cells. However, overexpression of SOX18 promoted cell proliferation, invasion, and migration, and inhibited cell apoptosis. The expression of cyclin D1, active-caspase-3, N-cadherin, MTA1, MMP-2, and MMP-7 was also regulated by the overexpression of siSOX18 or SOX18. In addition, it was found that SOX18 could also accelerate the phosphorylation of JAK2/STAT3 signaling in laryngeal carcinoma cells. Furthermore, our study indicated that SOX18 could stimulate cell proliferation, migration, and invasion of laryngeal carcinoma cells via regulation of JAK2/STAT3 signaling, which could provide a new strategy for laryngeal carcinoma diagnosis and molecular therapies.
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Down-regulation of SOX18 inhibits laryngeal carcinoma cell proliferation, migration, and invasion through JAK2/STAT3 signaling
Bioscience reports, 2019Co-Authors: Qingyuan Zhang, Jie Zhou, Junyu Guo, Weina Wang, Wei WangAbstract:Laryngeal carcinoma is one of the most common malignant tumors of the head, neck, and respiratory tract. The aim of the present study is to explore the biological function of SRY-related HMG-box 18 (SOX18) in laryngeal carcinoma cells and study the molecular mechanism involved. Initial findings indicate that the expression of SOX18 was increased in laryngeal carcinoma cell lines and tissues. The effect of SOX18 on laryngeal carcinoma cell proliferation, cell cycle, apoptosis, invasion, and migration was also identified. The results indicated that down-regulation of SOX18 significantly inhibited cell proliferation, migration, and invasion, and induced cell-cycle arrest in G0/G1 phase and apoptosis of laryngeal carcinoma cells. However, overexpression of SOX18 promoted cell proliferation, invasion, and migration, and inhibited cell apoptosis. The expression of cyclin D1, active-caspase-3, N-cadherin, MTA1, MMP-2, and MMP-7 was also regulated by the overexpression of siSOX18 or SOX18. In addition, it was found that SOX18 could also accelerate the phosphorylation of JAK2/STAT3 signaling in laryngeal carcinoma cells. Furthermore, our study indicated that SOX18 could stimulate cell proliferation, migration, and invasion of laryngeal carcinoma cells via regulation of JAK2/STAT3 signaling, which could provide a new strategy for laryngeal carcinoma diagnosis and molecular therapies.
George E.o. Muscat - One of the best experts on this subject based on the ideXlab platform.
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Effect of Disrupted SOX18 Transcription Factor Function on Tumor Growth, Vascularization, and Endothelial Development
Journal of the National Cancer Institute, 2006Co-Authors: Neville Young, Dagmar Wilhelm, Jane E. Olsson, George E.o. Muscat, Christopher N. Hahn, Alisa M Poh, Carolyn Dong, Peter G. Parsons, Jennifer R. Gamble, Peter KoopmanAbstract:Background. The growth of solid tumors depends on establishing blood supply; thus, inhibiting tumor angiogenesis has been a long-term goal in cancer therapy. The SOX18 transcription factor is a key regulator of murine and human blood vessel formation. Methods: We established allograft melanoma tumors in wild-type mice, SOX18-null mice, and mice expressing a dominant-negative form of SOX18 (SOX18RaOp) (n = 4 per group) and measured tumor growth and microvessel density by immunohistochemical analysis with antibodies to the endothelial marker CD31 and the pericyte marker NG2. We also assessed the affects of disrupted SOX18 function on MCF-7 human breast cancer and human umbilical vein endothelial cell (HUVEC) proliferation by measuring BrdU incorporation and by MTS assay, cell migration using Boyden chamber assay, and capillary tube formation in vitro. All statistical tests were two-sided. Results: Allograft tumors in SOX18-null and SOX18RaOp mice grew more slowly than those in wild-type mice (tumor volume at day 14, SOX18 null, mean = 486 mm(3), 95% confidence interval [CI] = 345 mm(3) to 627 mm(3), p = .004; SOX18RaOp, mean = 233 mm(3), 95% CI = 73 mm(3) to 119 mm(3), p < .001; versus wild-type, mean = 817 mm(3), 95% CI = 643 mm(3) to 1001 mm(3)) and had fewer CD31- and NG2-expressing vessels. Expression of dominant-negative SOX18 reduced the proliferation of MCF-7 cells (BrdU incorporation: MCF-7(Ra) = 20%, 95% CI = 15% to 25% versus MCF-7 = 41%, 95% CI = 35% to 45%; P = .013) and HUVECs (optical density at 490 nm, empty vector, mean = 0.46 versus SOX18 mean = 0.29; difference = 0.17, 95% CI = 0.14 to 0.19; P = .001) compared with control subjects. Overexpression of wild-type SOX18 promoted capillary tube formation of HUVECs in vitro, whereas expression of dominant-negative SOX18 impaired tube formation of HUVECs and the migration of MCF-7 cells via the disruption of the actin cytoskeleton. Conclusions: SOX18 is a potential target for antiangiogenic therapy of human cancers.
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the vcam 1 gene that encodes the vascular cell adhesion molecule is a target of the sry related high mobility group box gene SOX18
Journal of Biological Chemistry, 2004Co-Authors: Brett M. Hosking, Peter Koopman, Meredith Downes, S Mary C Wang, George E.o. MuscatAbstract:Abstract VCAM-1 (vascular cell adhesion molecule-1) and SOX18 are involved in vascular development. VCAM-1 is an important adhesion molecule that is expressed on endothelial cells and has a critical role in endothelial activation, inflammation, lymphatic pathophysiology, and atherogenesis. The Sry-related high mobility group box factor SOX18 has previously been implicated in endothelial pathologies. Mutations in human and mouse SOX18 leads to hypotrichosis and lymphedema. Furthermore, both SOX18 and VCAM-1 have very similar spatio-temporal patterns of expression, which is suggestive of cross-talk. We use biochemical techniques, cell culture systems, and the ragged opossum (RaOP) mouse model with a naturally occurring mutation in SOX18 to demonstrate that VCAM-1 is an important target of SOX18. Transfection, site-specific mutagenesis, and gel shift analyses demonstrated that SOX18 directly targeted and trans-activated VCAM-1 expression. Importantly, the naturally occurring SOX18 mutant attenuates the expression and activation of VCAM-1 in vitro. Furthermore, in vivo quantitation of VCAM-1 mRNA levels in wild type and RaOP mice demonstrates that RaOP animals show a dramatic and significant reduction in VCAM-1 mRNA expression in lung, skin, and skeletal muscle. Our observation that the VCAM-1 gene is an important target of SOX18 provides the first molecular insights into the vascular abnormalities in the mouse mutant ragged and the human hypotrichosislymphedema-telangiectasia disorder.
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SOX18 mutations in the ragged mouse alleles ragged-like and opossum.
Genesis (New York N.Y. : 2000), 2003Co-Authors: Kristy M. James, George E.o. Muscat, Brett M. Hosking, Jennifer M. Gardner, Peter KoopmanAbstract:The ragged (Ra) spontaneous mouse mutant is characterised by abnormalities in its coat and cardiovascular system. Four alleles are known and we have previously described mutations in the transcription factor gene SOX18 in the Ra and Ra(J) alleles. We report here SOX18 mutations in the remaining two ragged alleles, opossum (Ra(op)) and ragged-like (Ragl). The single-base deletions cause a C-terminal frameshift, abolishing transcriptional trans-activation and impairing interaction with the partner protein MEF2C. The nature of these mutations, together with the near-normal phenotype of SOX18-null mice, suggests that the ragged mutant SOX18 proteins act in a dominant-negative fashion. The four ragged mutants represent an allelic series that reveal SOX18 structure-function relationships and implicate related SOX proteins in cardiovascular and hair follicle development.
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SOX18 directly interacts with MEF2C in endothelial cells.
Biochemical and biophysical research communications, 2001Co-Authors: Brett M. Hosking, Peter Koopman, Sarah Penning, Sc Mary Wang, Shen Liang Chen, George E.o. MuscatAbstract:Recently, we demonstrated that mutations in the Sry-related HMG box gene SOX18 underlie vascular and hair follicle defects in the mouse allelic mutants ragged (Ra) and RaJ. Ra mice display numerous anomalies in the homozygote including, oedema, peritoneal secretions, and are almost completely naked. SOX18 and the MADS box transcription factor, Mef2C, are expressed in developing endothelial cells. Null mutants in SOX18 and Mef2c display overlapping phenotypic abnormalities, hence, we investigated the relationship between these two DNA binding proteins. We report here the direct interaction between MEF2C and SOX18 proteins, and establish that these proteins are coexpressed in vivo in endothelial cell nuclei. MEF2C expression potentiates SOX18-mediated transcription in vivo and regulates the function of the SOX18 activation domain. Interestingly, MEF2C fails to interact or co-activate transcription with the Ra or RaJ mutant SOX18 proteins. These results suggest that MEF2C and SOX18 may be important partners directing the transcriptional regulation of vascular development.
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SOX18 Is Transiently Expressed during Angiogenesis in Granulation Tissue of Skin Wounds with an Identical Expression Pattern to Flk-1 mRNA
Laboratory Investigation, 2001Co-Authors: Ian A Darby, George E.o. Muscat, Teresa Bisucci, Smiriti Raghoenath, Jane Olsson, Peter KoopmanAbstract:SOX18 encodes a member of the Sry -related high mobility group box (SOX) family of developmental transcription factors. Examination of SOX18 expression during embryogenesis has shown that SOX18 is expressed transiently in endothelial cells of developing blood vessels, and mutations in SOX18 have been found to underlie the mouse vascular and hair follicle mutant ragged. In this study we have examined the expression of SOX18 in angiogenesis during wound healing. Full-thickness skin wounds were created in mice, and subsequent expression of vascular endothelial growth factor (VEGF), the VEGF receptor Flk-1 , α1 (iv) collagen ( Col4a1 ), and SOX18 were studied using in situ hybridization. As has been previously reported, VEGF was expressed predominantly in the keratinocytes at the wound margins. SOX18 expression was found five days after wounding during capillary sprouting in granulation tissue and persisted through the proliferative phase of healing, but was not detected in fully epithelialized wounds 21 days after wounding. SOX18 mRNA expression was detected in capillaries within the granulation tissue and showed an identical pattern of distribution to Flk-1 and Col4a1 mRNA expression in endothelial cells. Immunostaining with a polyclonal anti- SOX18 antibody showed SOX18 protein localized in capillary endothelial cells within the granulation tissue. Capillaries in the subcutaneous tissue of unwounded skin showed no SOX18 expression. SOX18 may therefore represent a transcription factor involved in the induction of angiogenesis during wound healing and tissue repair, but not in the maintenance of endothelial cells in undamaged tissue.