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21.
Chiwaka Kimura Masayuki HayashiYuri Mizuno Masahiro Oike 《Biochimica et Biophysica Acta (BBA)/General Subjects》2013
Background
Induction of epithelial–mesenchymal transition (EMT) is essential for the metastasis of tumor cells and maintaining their stemness. This study aimed to examine whether endothelial cells, which are most closely located to tumor cells in vivo, play a role in inducing EMT in tumor cells or not.Methods
Concentrated culture medium of bovine aortic endothelial cells (BAECs) was applied to tumor cell lines (A549 and PANC-1) and epithelial cell line (NMuMg). Cadherin conversion, expressions of α-smooth muscle actin and ZO-1, actin fiber formation and cell migration were examined as hallmarks of the induction of EMT in these cell lines. Transforming growth factor β (TGFβ) antibodies were used to neutralize TGFβ1, TGFβ2 and TGFβ3. Expression and release of TGFβ proteins in BAECs as well as in porcine and human endothelial cells were assessed by Western blotting and ELISA, respectively.Results
Conditioned medium of BAEC induced EMT in the examined cell lines. All endothelial cells from various species and locations expressed TGFβ1 and TGFβ2 proteins and much lower level of TGFβ3 protein. Conditioned medium from these endothelial cells contained TGFβ1 and TGFβ2, but TGFβ3 could not be detected. Neutralizing antibody against each of TGFβ1 or TGFβ2 did not reverse endothelium-dependent EMT, but simultaneous neutralization of both TGFβ1 and TGFβ2 completely abolished it.Conclusions
Endothelial cells may play a role in the induction and maintenance of EMT in tumor cells by constitutively releasing TGFβ1 and TGFβ2.General significance
The present results provide a novel strategy of the inhibition of tumor metastasis by targeting vascular endothelium. 相似文献22.
Involvement of proteinase-activated receptor-2 in mast cell tryptase-induced barrier dysfunction in bovine aortic endothelial cells 总被引:6,自引:0,他引:6
Sendo T Sumimura T Itoh Y Goromaru T Aki K Yano T Oike M Ito Y Mori S Nishibori M Oishi R 《Cellular signalling》2003,15(8):773-781
We report here a direct modulation by mast cell tryptase of endothelial barrier function through activation of proteinase-activated receptor-2 (PAR-2). In cultured bovine aortic endothelial cells (BAECs), tryptase, trypsin and PAR-2 activating peptide impaired the barrier function as determined by the permeability of protein-conjugated Evans blue. The tryptase-induced barrier dysfunction was completely blocked by U73122, and partially reversed by xestospongin C, calphostin C or Y27632. The intracellular Ca(2+) was elevated by tryptase. It was notable that ioxaglate, a contrast material that degranulates mast cells, markedly increased the permeability when applied to BAECs in combination with mast cells, an action that was blocked by nafamostat, a potent tryptase inhibitor. Immunofluorescence analysis showed that actin stress fibre formation and disruption of VE-cadherin were observed after exposure to tryptase or ioxaglate in combination with mast cells. Therefore, it is suggested that mast cell tryptase impairs endothelial barrier function through activation of endothelial PAR-2 in a manner dependent on the phospholipase C activity. 相似文献
23.
Li Z Takakura N Oike Y Imanaka T Araki K Suda T Kaname T Kondo T Abe K Yamamura K 《Development, growth & differentiation》2003,45(5-6):449-462
The qkI gene encodes an RNA binding protein which was identified as a candidate for the classical neurologic mutation, qkv. Although qkI is involved in glial cell differentiation in mice, qkI homologues in other species play important roles in various developmental processes. Here, we show a novel function of qkI in smooth muscle cell differentiation during embryonic blood vessel formation. qkI null embryos died between embryonic day 9.5 and 10.5. Embryonic day 9.5 qkI null embryos showed a lack of large vitelline vessels in the yolk sacs, kinky neural tubes, pericardial effusion, open neural tubes and incomplete embryonic turning. Using X-gal and immunohistochemical staining, qkI is first shown to be expressed in endothelial cells and smooth muscle cells. Analyses of qkI null embryos in vivo and in vitro revealed that the vitelline artery was too thin to connect properly to the yolk sac, thereby preventing remodeling of the yolk sac vasculature, and that the vitelline vessel was deficient in smooth muscle cells. Addition of QKI and platelet-endothelial cell adhesion molecule-1 positive cells to an in vitro para-aortic splanchnopleural culture of qkI null embryos rescued the vascular remodeling deficit. These data suggest that QKI protein has a critical regulatory role in smooth muscle cell development, and that smooth muscle cells play an important role in inducing vascular remodeling. 相似文献
24.
Miyata K Oike Y Hoshii T Maekawa H Ogawa H Suda T Araki K Yamamura K 《Biochemical and biophysical research communications》2005,329(1):296-304
Multiple steps, including the migration of vascular smooth muscle cells (SMCs), are involved in the pathogenesis of atherosclerosis. To discover genes which are involved in these steps, we screened mutant mouse lines established by the exchangeable gene trap method utilizing X-gal staining during their embryonic development. One of these lines showed strong reporter gene expression in the vitelline vessels of yolk sacs at embryonic day (E) 12.5. The trap vector was inserted into the fifth intron of alpha/beta hydrolase domain containing 2 (Abhd2) gene which was shown to be expressed in vascular and non-vascular SMCs of adult mice. Although homozygous mutant mice were apparently normal, enhanced SMC migration in the explants SMCs culture and marked intimal hyperplasia after cuff placement were observed in homozygous mice in comparison with wild-type mice. Our results show that Abhd2 is involved in SMC migration and neointimal thickening on vascular SMCs. 相似文献
25.
Yuasa H Takakura N Shimomura T Suenobu S Yamada T Nagayama H Oike Y Suda T 《Biochemical and biophysical research communications》2002,298(5):731-737
To investigate the behavior of hematopoietic stem cells (HSCs) in cord blood (CB), we analyzed the expression and function of TIE2, a tyrosine kinase receptor. A subpopulation of Lineage (Lin)(-/low)CD34(+) cells in CB expressed TIE2 (18.8%). Assays for long-term culture-initiating cells (LTC-IC) and cobble-stone formation revealed that Lin(-/low)CD34(+)TIE2(+) cells showed to have a capacity of primitive hematopoietic precursor cells in vitro. When Lin(-/low)CD34(+)TIE2(+) cells were cultured on the stromal cells, they transmigrated under the stromal layers and kept an immature character for a few weeks. By contrast, Lin(-/low)CD34(+)TIE2(-) cells differentiated immediately within a few weeks. Finally, we confirmed that 1x10(4)Lin(-/low)CD34(+)TIE2(+) cells were engrafted in non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice, while 1x10(4)Lin(-/low)CD34(+)TIE2(-) cells were not. Taken together, we conclude that TIE2 is a marker of HSCs in CB. A ligand for TIE2, Ang-1 promoted the adhesion of sorted primary Lin(-/low)CD34(+)TIE2(+) cells to fibronectin (FN), and this adhesion may play a critical role in keeping HSCs in an immature status under the stromal cells. 相似文献
26.
The profibrinolytic enzyme subtilisin NAT purified from Bacillus subtilis Cleaves and inactivates plasminogen activator inhibitor type 1 总被引:22,自引:0,他引:22
Urano T Ihara H Umemura K Suzuki Y Oike M Akita S Tsukamoto Y Suzuki I Takada A 《The Journal of biological chemistry》2001,276(27):24690-24696
In this report, we demonstrate an interaction between subtilisin NAT (formerly designated BSP, or nattokinase), a profibrinolytic serine proteinase from Bacillus subtilis, and plasminogen activator inhibitor 1 (PAI-1). Subtilisin NAT was purified to homogeneity (molecular mass, 27.7 kDa) from a saline extract of B. subtilis (natto). Subtilisin NAT appeared to cleave active recombinant prokaryotic PAI-1 (rpPAI-1) into low molecular weight fragments. Matrix-assisted laser desorption/ionization in combination with time-of-flight mass spectroscopy and peptide sequence analysis revealed that rpPAI-1 was cleaved at its reactive site (P1-P1': Arg(346)-Met(347)). rpPAI-1 lost its specific activity after subtilisin NAT treatment in a dose-dependent manner (0.02-1.0 nm; half-maximal effect at approximately 0.1 nm). Subtilisin NAT dose dependently (0.06-1 nm) enhanced tissue-type plasminogen activator-induced fibrin clot lysis both in the absence of rpPAI-1 (48 +/- 1.4% at 1 nm) and especially in the presence of rpPAI-1 (78 +/- 2.0% at 1 nm). The enhancement observed in the absence of PAI-1 seems to be induced through direct fibrin dissolution by subtilisin NAT. The stronger enhancement by subtilisin NAT of rpPAI-1-enriched fibrin clot lysis seems to involve the cleavage and inactivation of active rpPAI-1. This mechanism is suggested to be important for subtilisin NAT to potentiate fibrinolysis. 相似文献
27.
Kubota T Kubota N Kumagai H Yamaguchi S Kozono H Takahashi T Inoue M Itoh S Takamoto I Sasako T Kumagai K Kawai T Hashimoto S Kobayashi T Sato M Tokuyama K Nishimura S Tsunoda M Ide T Murakami K Yamazaki T Ezaki O Kawamura K Masuda H Moroi M Sugi K Oike Y Shimokawa H Yanagihara N Tsutsui M Terauchi Y Tobe K Nagai R Kamata K Inoue K Kodama T Ueki K Kadowaki T 《Cell metabolism》2011,13(3):294-307
In obese patients with type 2 diabetes, insulin delivery to and insulin-dependent glucose uptake by skeletal muscle are delayed and impaired. The mechanisms underlying the delay and impairment are unclear. We demonstrate that impaired insulin signaling in endothelial cells, due to reduced Irs2 expression and insulin-induced eNOS phosphorylation, causes attenuation of insulin-induced capillary recruitment and insulin delivery, which in turn reduces glucose uptake by skeletal muscle. Moreover, restoration of insulin-induced eNOS phosphorylation in endothelial cells completely reverses the reduction in capillary recruitment and insulin delivery in tissue-specific knockout mice lacking Irs2 in endothelial cells and fed a high-fat diet. As a result, glucose uptake by skeletal muscle is restored in these mice. Taken together, our results show that insulin signaling in endothelial cells plays a pivotal role in the regulation of glucose uptake by skeletal muscle. Furthermore, improving endothelial insulin signaling may serve as a therapeutic strategy for ameliorating skeletal muscle insulin resistance. 相似文献
28.
Masato Yano Tadashi Yamamoto Naotaka Nishimura Tomomi Gotoh Ken Watanabe Kazutaka Ikeda Yohei Garan Ryo Taguchi Koichi Node Toshiro Okazaki Yuichi Oike 《PloS one》2013,8(4)
Sphingomyelin synthase 1 (SMS1) catalyzes the conversion of ceramide to sphingomyelin. Here, we found that SMS1 null mice showed lipodystrophic phenotype. Mutant mice showed up-regulation of plasma triglyceride concentrations accompanied by reduction of white adipose tissue (WAT) as they aged. Lipoprotein lipase (LPL) activity was severely reduced in mutant mice. In vivo analysis indicated that fatty acid uptake in WAT but not in liver decreased in SMS1 null compared to wild-type mice. In vitro analysis using cultured cell revealed that SMS1 depletion reduced fatty acid uptake. Proteins extracted from WAT of mutant mice were severely modified by oxidative stress, and up-regulation of mRNAs related to apoptosis, redox adjustment, mitochondrial stress response and mitochondrial biogenesis was observed. ATP content of WAT was reduced in SMS1 null mice. Blue native gel analysis indicated that accumulation of mitochondrial respiratory chain complexes was reduced. These results suggest that WAT of SMS1 null mice is severely damaged by oxidative stress and barely functional. Indeed, mutant mice treated with the anti-oxidant N-acetyl cysteine (NAC) showed partial recovery of lipodystrophic phenotypes together with normalized plasma triglyceride concentrations. Altogether, our data suggest that SMS1 is crucial to control oxidative stress in order to maintain WAT function. 相似文献
29.
Spreds are essential for embryonic lymphangiogenesis by regulating vascular endothelial growth factor receptor 3 signaling 总被引:9,自引:0,他引:9 下载免费PDF全文
Taniguchi K Kohno R Ayada T Kato R Ichiyama K Morisada T Oike Y Yonemitsu Y Maehara Y Yoshimura A 《Molecular and cellular biology》2007,27(12):4541-4550
Spred/Sprouty family proteins negatively regulate growth factor-induced ERK activation. Although the individual physiological roles of Spred-1 and Spred-2 have been investigated using gene-disrupted mice, the overlapping functions of Spred-1 and Spred-2 have not been clarified. Here, we demonstrate that the deletion of both Spred-1 and Spred-2 resulted in embryonic lethality at embryonic days 12.5 to 15.5 with marked subcutaneous hemorrhage, edema, and dilated lymphatic vessels filled with erythrocytes. This phenotype resembled that of Syk−/− and SLP-76−/− mice with defects in the separation of lymphatic vessels from blood vessels. The number of LYVE-1-positive lymphatic vessels and lymphatic endothelial cells increased markedly in Spred-1/2-deficient embryos compared with WT embryos, while the number of blood vessels was not different. Ex vivo colony assay revealed that Spred-1/2 suppressed lymphatic endothelial cell proliferation and/or differentiation. In cultured cells, the overexpression of Spred-1 or Spred-2 strongly suppressed vascular endothelial growth factor-C (VEGF-C)/VEGF receptor (VEGFR)-3-mediated ERK activation, while Spred-1/2-deficient cells were extremely sensitive to VEGFR-3 signaling. These data suggest that Spreds play an important role in lymphatic vessel development by negatively regulating VEGF-C/VEGFR-3 signaling. 相似文献
30.
Hiro Sato Yoshiyuki Suzuki Munenori Ide Toshihide Katoh Shin-ei Noda Ken Ando Takahiro Oike Yuya Yoshimoto Noriyuki Okonogi Kousaku Mimura Takayuki Asao Hiroyuki Kuwano Takashi Nakano 《PloS one》2014,9(9)