RESUMO
Polymorphism of genes of transforming growth factor TGFB and its receptors (TGFBRI, TGFBRII, and TGFBRIIII) in patients with primary open-angle glaucoma was analyzed. The frequency of the TGFBRII CC genotype in patients is increased relative to the control group (OR=6.10, p=0.0028). Heterozygosity in this polymorphic position is reduced (OR=0.18, p=0.0052). As the effects of TGF-ß is mediated through its receptors, we analyzed complex of polymorphic variants of the studied loci in the genome of patients. Two protective complexes consisting only of receptor genes were identified: TGFBRI TT:TGFBRII CG (OR=0.10, p=0.02) and TGFBRII CG:TGFBRIII CG (OR=0.09, p=0.01). The study showed an association of TGFBRII polymorphism with primary open-angle glaucoma and the need to study functionally related genes in the development of the disease, which should contribute to its early diagnosis and prevention.
Assuntos
Glaucoma de Ângulo Aberto , Humanos , Glaucoma de Ângulo Aberto/genética , Feminino , Masculino , Pessoa de Meia-Idade , Sibéria , Idoso , Polimorfismo de Nucleotídeo Único/genética , Predisposição Genética para Doença/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Frequência do Gene/genética , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Estudos de Casos e Controles , Genótipo , Fator de Crescimento Transformador beta/genética , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Polimorfismo Genético/genéticaRESUMO
Regeneration is a unique defense mechanism of liver tissue in response to functional cell loss induced by toxic chemicals or surgical resection. In this study, we found that Islet-cell autoantigen 69 (Ica69) accelerates liver regeneration in mice. Following 70% partial hepatectomy, both Ica69 mRNA and protein are significantly upregulated in mouse hepatocytes at the early stage of liver regeneration. Compared with the wild-type mice, Ica69-deficient mice have more severe liver injury, delayed liver regeneration, and high surgical accidental mortality following hepatectomy. Mechanistically, Ica69 interacts with Pick1 protein to regulate Tgfbr1 protein expression and Tgfß-induced Smad2 phosphorylation. Our findings suggest that Ica69 in liver tissue is a new potential target for promoting liver regeneration.
Assuntos
Autoantígenos/genética , Hepatócitos/metabolismo , Regeneração Hepática/genética , Fígado/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Fator de Crescimento Transformador beta/genética , Animais , Autoantígenos/metabolismo , Sítios de Ligação , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Regulação da Expressão Gênica , Hepatectomia/métodos , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Fígado/citologia , Fígado/cirurgia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação/efeitos dos fármacos , Cultura Primária de Células , Ligação Proteica , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Transdução de Sinais , Proteína Smad2/genética , Proteína Smad2/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta/farmacologiaRESUMO
The transforming growth factor-ß (TGF-ß) signaling pathway is conserved across animals, and knowledge of its roles during the molt cycle in crustaceans is presently very limited. This study investigates the roles of the TGF-ß receptor in molting-related muscle growth in Eriocheir sinensis. Using the RT-PCR and RACE techniques, we obtained a 1722 bp cDNA sequence encoding a transforming growth factor-ß type I receptor in Eriocheir sinensis, designated EsTGFBRI, which contains a 124 bp 5'-untranslated region, a 20 bp partial 3'-untranslated region and a 1578 bp open reading frame encoding 525 amino acids. The deduced EsTGFBRI contains an N-terminal 24 amino acid signal peptide, an activin type I and II receptor domain, a transmembrane helix region, a glycine-serine-rich motif, and a conserved serine/threonine kinase catalytic domain including an activation loop. The qRT-PCR results showed that EsTGFBRI gene was highly expressed in the intermolt testis and ovary in mature crabs. In juvenile crabs, the mRNA levels of EsTGFBRI in claw and abdominal muscles in the later premolt D3-4 stage were significantly higher than those in the intermolt C and postmolt A-B stages. There was no significant change in EsTGFBRI mRNA levels in walking leg muscles during the molt cycle. The results suggest that EsTGFBRI is probably play roles in molting-related muscle growth in E. sinensis. This study provides a necessary basis for elucidating the functions of TGF-ß-like signaling mediated by TGFBRI in molting-related muscle growth in crustaceans.
Assuntos
Braquiúros/genética , Muda/genética , Músculo Esquelético/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Braquiúros/classificação , Braquiúros/metabolismo , Clonagem Molecular , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Masculino , Modelos Moleculares , Músculo Esquelético/crescimento & desenvolvimento , Filogenia , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Receptor do Fator de Crescimento Transformador beta Tipo I/química , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Transdução de Sinais/genética , Fator de Crescimento Transformador beta1/metabolismoRESUMO
BACKGROUND: Wilms' tumor is also called nephroblastoma and is the most common pediatric renal cancer. Several genetic and epigenetic factors have been found to account for the development of Wilms' tumor. MiRNAs play important roles in this tumorigenic process. In the present study, we aimed to investigate the role of miR-140-5p in nephroblastoma by identifying its targets, as well as its underlying molecular mechanism of action. METHODS: The miRNA expression profile of nephroblastoma samples was investigated and the targets of miR-140-5p were predicted and validated using the miRNA luciferase reporter method. Moreover, the roles of miR-140-5p in regulating nephroblastoma cell proliferation, migration and cell cycle were analyzed by the CCK8, migration and flow cytometry assays, respectively. The downstream protein of the direct target of miR-140-5p was also identified. RESULTS: miR-140-5p was downregulated in Wilms' tumor tissues, whereas in the nephroblastoma cell lines G401 and WT-CLS1 that exhibited high levels of miRNA-140-5p, inhibition of cellular proliferation and metastasis were noted as well as cell cycle arrest at the G1/S phase. TGFBRI and IGF1R were identified as direct target genes for miRNA-140-5p. In addition, SMAD2/3 and p-AKT were regulated by TGFBRI and IGF1R separately and participated in the miRNA-140-5p regulatory network. Ectopic expression of TGFBR1 and IGF-1R could abrogate the inhibitory effect of miR-140-5p. CONCLUSION: We demonstrated that miRNA-140-5p participates in the progression of Wilms' tumor by targeting the TGFBRI/SMAD2/3 and the IGF-1R/AKT signaling pathways.
