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1.
Mol Cell Endocrinol ; 508: 110790, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32165171

RESUMO

The tumor suppressor gene Reversion-inducing cysteine-rich protein with Kazal motifs (Reck) encodes a membrane-anchored protease regulator expressed in multiple tissues in mouse embryos and is essential for embryonic development. In postnatal mice, however, physiological roles for the RECK protein remain unclear. We found in this study that Reck is abundantly expressed in growth hormone (GH)-producing cells (somatotrophs) in the anterior pituitary gland (AP). We also found that two types of viable Reck mutant mice, one with reduced RECK expression (Hypo mice) and the other with induced Reck deficiency from 10 days after birth (iKO mice treated with tamoxifen), exhibit common phenotypes including decreases in body size and plasma levels of insulin-like growth factor-1 (IGF1). To gain insights into the function of RECK in the AP, we characterized several somatotroph-associated molecules in the AP of these mice. Immunoreactivity of GH was greatly reduced in tamoxifen-treated iKO mice; in these mice, two membrane receptors involved in the stimulation of GH secretion [growth hormone secretagogue receptor (GHSR) and growth hormone releasing hormone receptor (GHRHR)] were decreased, however, their mRNAs were increased. Decrease in GHSR immunoreactivity and concomitant increase in its mRNA were also found in the other mutant line, Hypo. Furthermore, reduced immunoreactivity of growth hormone receptor (GHR) and concomitant increase in its mRNA was also found in the liver of Hypo mice. These results raise the possibility that RECK supports proper functioning of the GH/IGF1 axis in mice, thereby affecting their growth and metabolism.


Assuntos
Proteínas Ligadas por GPI/metabolismo , Hormônio do Crescimento/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Adeno-Hipófise/metabolismo , Transdução de Sinais , Animais , Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Núcleo Arqueado do Hipotálamo/metabolismo , Proteínas Ligadas por GPI/genética , Hormônio do Crescimento Humano/metabolismo , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos Knockout , Mutação/genética , Octreotida/farmacologia , Oligopeptídeos/farmacologia , Fenótipo , Receptores Acoplados a Proteínas G/metabolismo , Somatotrofos/metabolismo
2.
Sci Rep ; 8(1): 7493, 2018 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-29748547

RESUMO

Matrix-assisted laser desorption ionization image mass spectrometry (MALDI-IMS) has been developed for the identification of peptides in various tissues. The MALDI-IMS signal distribution patterns and quantification of the signal intensities of the regions of interest (ROI) with healthy regions were compared for identification of the disease specific biomarkers. We performed a new ROI analysis using the conventional t-test and data number independent Cohen's d-value analysis. Using these techniques, we analysed heart tissues after acute myocardial infarction (AMI). As a result, IMS signals of mitochondrial adenosine triphosphate synthase alpha subunit (ATP5A), myosin-6/7(MYH6/7), aortic actin, and the myosin light chain 3 (MYL3) were identified in the infarcted region. In particular, the signals of MYH7 are significantly greater in the infarcted region using ROI analysis. ROI analysis using MALDI-IMS may be a promising technique for the identification of biomarkers for pathological studies that involve the comparison of diseased and control areas.


Assuntos
Mitocôndrias Cardíacas/metabolismo , Proteínas Mitocondriais/metabolismo , Proteínas Musculares/metabolismo , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Sarcômeros/metabolismo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Autopsia , Biomarcadores/análise , Biomarcadores/metabolismo , Estudos de Casos e Controles , Humanos , Mitocôndrias Cardíacas/patologia , Proteínas Mitocondriais/análise , Proteínas Musculares/análise , Sarcômeros/patologia , Remodelação Vascular , Remodelação Ventricular
3.
Genesis ; 56(4): e23099, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29508517

RESUMO

Reck encodes a membrane-anchored glycoprotein implicated in the regulation of extracellular metalloproteinases, Notch-signaling, and Wnt7-signaling and shown to play critical roles in embryogenesis and tumor suppression. Precise mechanisms of its actions in vivo, however, remain largely unknown. By homologous recombination, we generated a new Reck allele, ReckCreERT2 (MGI symbol: Reck). This allele is defective in terms of Reck function but expected to induce loxP-mediated recombination in the cells committed to express Reck. Similarity in the expression patterns of the ReckCreERT2 transgene and the endogenous Reck gene was confirmed in five tissues. In the adult hippocampus, induction of Reck expression after transient cerebral ischemia could be demonstrated using this allele. These results indicate the utility of this Cre-driver allele in further studies.


Assuntos
Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Alelos , Animais , Técnicas de Introdução de Genes , Engenharia Genética/métodos , Integrases/genética , Camundongos , Transdução de Sinais
5.
Sci Rep ; 5: 17860, 2015 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-26658478

RESUMO

Extracellular matrix (ECM) is known to play several important roles in vascular development, although the molecular mechanisms behind these remain largely unknown. RECK, a tumor suppressor downregulated in a wide variety of cancers, encodes a membrane-anchored matrix-metalloproteinase-regulator. Mice lacking functional Reck die in utero, demonstrating its importance for mammalian embryogenesis; however, the underlying causes of mid-gestation lethality remain unclear. Using Reck conditional knockout mice, we have now demonstrated that the lack of Reck in vascular mural cells is largely responsible for mid-gestation lethality. Experiments using cultured aortic explants further revealed that Reck is essential for at least two events in sprouting angiogenesis; (1) correct association of mural and endothelial tip cells to the microvessels and (2) maintenance of fibronectin matrix surrounding the vessels. These findings demonstrate the importance of appropriate cell-cell interactions and ECM maintenance for angiogenesis and the involvement of Reck as a critical regulator of these events.


Assuntos
Vasos Sanguíneos/metabolismo , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Neovascularização Fisiológica/genética , Alelos , Animais , Matriz Extracelular/metabolismo , Feminino , Fibronectinas/metabolismo , Proteínas Ligadas por GPI/deficiência , Inativação Gênica , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Microvasos/metabolismo , Mutação , Especificidade de Órgãos/genética
6.
Nat Commun ; 6: 6748, 2015 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-25849081

RESUMO

Accumulating evidence suggests that viruses play an important role in the development of diabetes. Although the diabetogenic encephalomyocarditis strain D virus induces diabetes in restricted lines of inbred mice, the susceptibility genes to virus-induced diabetes have not been identified. We report here that novel Tyrosine kinase 2 (Tyk2) gene mutations are present in virus-induced diabetes-sensitive SJL and SWR mice. Mice carrying the mutant Tyk2 gene on the virus-resistant C57BL/6 background are highly sensitive to virus-induced diabetes. Tyk2 gene expression is strongly reduced in Tyk2-mutant mice, associated with low Tyk2 promoter activity, and leads to decreased expression of interferon-inducible genes, resulting in significantly compromised antiviral response. Tyk2-mutant pancreatic ß-cells are unresponsive even to high dose of Type I interferon. Reversal of virus-induced diabetes could be achieved by ß-cell-specific Tyk2 gene expression. Thus, reduced Tyk2 gene expression in pancreatic ß-cells due to natural mutation is responsible for susceptibility to virus-induced diabetes.


Assuntos
Infecções por Cardiovirus/genética , Diabetes Mellitus Experimental/genética , Vírus da Encefalomiocardite , Células Secretoras de Insulina/metabolismo , RNA Mensageiro/metabolismo , TYK2 Quinase/genética , Animais , Diabetes Mellitus Experimental/virologia , Expressão Gênica , Predisposição Genética para Doença , Interferon Tipo I , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Camundongos Knockout , Mutação , TYK2 Quinase/metabolismo
7.
Arch Virol ; 153(7): 1223-31, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18500429

RESUMO

In order to clarify the significance of protective mechanisms against encephalomyocarditis (EMC) virus-induced diabetes in mice, we studied the relative importance of T cells, B cells, antibodies and macrophages in the prevention of virus-induced diabetes. Neither T cell-deficient athymic nude mice nor B cell-deficient microMT/microMT mice showed an enhanced clinical course of EMC-D virus-induced diabetes, indicating that neither T cells nor B cells played a major role in the protection against EMC-D-virus-induced diabetes. Transfer of a large amount of antiserum to EMC-D-virus-infected mice protected the development of diabetes only when transferred within 36 h of infection, the timing of which was earlier than that for the production of natural neutralizing antibodied. Since pretreatment of mice with the macrophage-activating immunopotentiator Corynebacterium parvum (CP) completely prevented the development of diabetes, we studied the clinical outcome of EMC-D-virus-infected mice pretreated with CP. Mice treated with CP showed reduced proliferation of EMC-D virus in the affected organs, including the pancreas, while the levels of development of neutralizing antibody and serum interferon were not enhanced compared with the controls. Finally, we studied the macrophages derived from mice pretreated with CP and found that they inhibited the growth of EMC-D virus in vitro more than those derived from non-treated and thioglycolate-treated mice. Taken together, it can be suggested that neither T cells nor B cells, which have to do with adaptive immunity, play a significant role in the pathogenesis of EMC-D-virus-induced diabetes, while innate immunity, which is dependent on activated macrophages, contributes to in vivo resistance against EMC-D-virus-induced diabetes.


Assuntos
Anticorpos Antivirais/imunologia , Infecções por Cardiovirus/complicações , Infecções por Cardiovirus/imunologia , Diabetes Mellitus Tipo 1/prevenção & controle , Vírus da Encefalomiocardite/imunologia , Linfócitos/imunologia , Macrófagos/imunologia , Animais , Anticorpos Antivirais/sangue , Anticorpos Antivirais/uso terapêutico , Glicemia/análise , Interferons/sangue , Masculino , Camundongos , Camundongos Endogâmicos DBA , Camundongos Nus , Testes de Neutralização , Propionibacterium acnes/imunologia
8.
Chem Commun (Camb) ; (20): 2118-20, 2006 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-16703126

RESUMO

Microarray screening of polymer libraries for cellular adhesion was developed utilising a thin film of agarose to allow unsurpassed localisation of cell binding onto the array substrate and the discovery of cell specific polymers.


Assuntos
Adesão Celular/fisiologia , Células Epiteliais/citologia , Análise em Microsséries/métodos , Polímeros/química , Humanos
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