Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 20.741
Filtrar
1.
Exp Suppl ; 111: 385-416, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31588541

RESUMO

In addition to the common types of diabetes mellitus, two major monogenic diabetes forms exist. Maturity-onset diabetes of the young (MODY) represents a heterogenous group of monogenic, autosomal dominant diseases. MODY accounts for 1-2% of all diabetes cases, and it is not just underdiagnosed but often misdiagnosed to type 1 or type 2 diabetes. More than a dozen MODY genes have been identified to date, and their molecular classification is of great importance in the correct treatment decision and in the judgment of the prognosis. The most prevalent subtypes are HNF1A, GCK, and HNF4A. Genetic testing for MODY has changed recently due to the technological advancements, as contrary to the sequential testing performed in the past, nowadays all MODY genes can be tested simultaneously by next-generation sequencing. The other major group of monogenic diabetes is neonatal diabetes mellitus which can be transient or permanent, and often the diabetes is a part of a syndrome. It is a severe monogenic disease appearing in the first 6 months of life. The hyperglycemia usually requires insulin. There are two forms, permanent neonatal diabetes mellitus (PNDM) and transient neonatal diabetes mellitus (TNDM). In TNDM, the diabetes usually reverts within several months but might relapse later in life. The incidence of NDM is 1:100,000-1:400,000 live births, and PNDM accounts for half of the cases. Most commonly, neonatal diabetes is caused by mutations in KCNJ11 and ABCC8 genes encoding the ATP-dependent potassium channel of the ß cell. Neonatal diabetes has experienced a quick and successful transition into the clinical practice since the discovery of the molecular background. In case of both genetic diabetes groups, recent guidelines recommend genetic testing.


Assuntos
Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus/genética , Doenças do Recém-Nascido/genética , Testes Genéticos , Fator 1-alfa Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/genética , Humanos , Recém-Nascido , Mutação , Canais de Potássio Corretores do Fluxo de Internalização/genética , Proteínas Serina-Treonina Quinases/genética , Receptores Sulfonilureia/genética
2.
J Cancer Res Clin Oncol ; 145(10): 2413-2422, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31492983

RESUMO

PURPOSE: Polo-like kinase 4 (PLK4) is a serine/threonine protein kinase that regulates centriole duplication. PLK4 deregulation causes centrosome number abnormalities, mitotic defects, chromosomal instability and, consequently, tumorigenesis. Therefore, PLK4 has emerged as a therapeutic target for the treatment of multiple cancers. In this review, we summarize the critical role of centrosome amplification and PLK4 in cancer. We also highlight recent advances in the development of PLK4 inhibitors and discuss potential combination therapies for cancer. METHODS: The relevant literature from PubMed is reviewed in this article. The ClinicalTrials.gov database was searched for clinical trials related to the specific topic. RESULTS: PLK4 is aberrantly expressed in multiple cancers and has prognostic value. Targeting PLK4 with inhibitors suppresses tumor growth in vitro and in vivo. CONCLUSIONS: PLK4 plays an important role in centrosome amplification and tumor progression. PLK4 inhibitors used alone or in combination with other drugs have shown significant anticancer efficacy, suggesting a potential therapeutic strategy for cancer. The results of relevant clinical trials await evaluation.


Assuntos
Biomarcadores Tumorais , Neoplasias/etiologia , Neoplasias/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Centrossomo/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Terapia de Alvo Molecular , Metástase Neoplásica , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Especificidade de Órgãos/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/genética , Relação Estrutura-Atividade , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
3.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(9): 862-865, 2019 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-31515776

RESUMO

OBJECTIVE: To screen for pathogenic variants in the coding regions of STK11 gene among Chinese patients with Peutz-Jeghers syndrome (PJS). METHODS: Peripheral blood samples were collected from 64 patients. The coding regions of the STK11 gene were detected by PCR and Sanger sequencing. RESULTS: Fourty-eight patients were found to harbor STK11 gene variants, which included 39 types of variants consisting of missense, nonsense, insertional, deletional and splice site variants. Among 64 PJS patients, the detection rate of point variants was 75.00% (48/64), of which missense variants accounted for 29.17% (14/48), nonsense variants accounted for 29.17%(14/48), insertion variants accounted for 2.08% (1/48), deletional variants accounted for 10.42% (5/48), and splice site variants accounted for 29.17% (14/48). The detection rates of sporadic cases and those with a family history were 71.8% (28/39) and 80.0% (20/25), respectively. Two variants (c.250A>T, c.580G>A) occurred in 3 PJS probands. Thirteen variants were unreported previously and were considered to be pathogenic. CONCLUSION: The detection rate of variants among Chinese PJS patients is similar to that of other countries. A number of novel common variant sites were discovered, which enriched the spectrum of PJS-related variants.


Assuntos
Síndrome de Peutz-Jeghers/genética , Proteínas Serina-Treonina Quinases/genética , Grupo com Ancestrais do Continente Asiático , China , Análise Mutacional de DNA , Humanos
4.
J Agric Food Chem ; 67(35): 9757-9771, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31373492

RESUMO

BAK1 effects on plant stress responses have been well documented, but little is known regarding its effects on plant growth. In this study, we functionally characterized MdBAK1. Overexpressing MdBAK1 in Arabidopsis thaliana and apple trees promoted growth. Longitudinal stem cells were longer in transgenic plants than in wild-type plants. The size and number of cells and the area of the transverse stem were greater in the transgenic lines than in the wild-type plants. Moreover, transgenic A. thaliana and apple plants were more sensitive to an exogenous brassinosteroid. A transcriptome analysis of wild-type and transgenic apple revealed that MdBAK1 overexpression activated the brassinosteroid and ethylene signals, xylem production, and stress responses. Trend and Venn analyses indicated that carbohydrate, energy, and hormone metabolic activities were greater in transgenic plants during different periods. Moreover, a weighted gene coexpression network analysis proved that carbohydrate, hormone, and xylem metabolism as well as cell growth may be critical for MdBAK1-mediated apple tree growth and development. Compared with the corresponding levels in wild-type plants, the endogenous brassinosteroid, cytokinin, starch, sucrose, trehalose, glucose, fructose, and total sugar contents were considerably different in transgenic plants. Our results imply that MdBAK1 helps to regulate the growth of apple tree through the above-mentioned pathways. These findings provide new information regarding the effects of MdBAK1 onplant growth and development.


Assuntos
Arabidopsis/crescimento & desenvolvimento , Arabidopsis/genética , Malus/crescimento & desenvolvimento , Proteínas de Plantas/metabolismo , Plantas Geneticamente Modificadas/crescimento & desenvolvimento , Proteínas Serina-Treonina Quinases/metabolismo , Arabidopsis/metabolismo , Brassinosteroides/metabolismo , Etilenos/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Malus/genética , Malus/metabolismo , Proteínas de Plantas/genética , Plantas Geneticamente Modificadas/genética , Plantas Geneticamente Modificadas/metabolismo , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais
5.
DNA Cell Biol ; 38(8): 824-839, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31295023

RESUMO

Tea plant is an important economic crop on a global scale. Its yield and quality are affected by abiotic stress. The calcineurin B-like protein (CBL) and CBL-interacting protein kinase (CIPK) family genes play irreplaceable roles in plant development and stress resistance. More and more CBL-CIPK genes have been identified, but a few CBL-CIPK genes have been cloned and characterized in tea plants. In this study, 7 CsCBLs and 18 CsCIPKs were identified based on the tea plant genome. Physicochemical properties, phylogenetic, conserved motifs, gene structure, homologous gene network, and promoter upstream elements of these 25 genes were analyzed. Conserved motifs of these genes varied with phylogenetic tree node. From the genetic structure, members of the tea plant CIPK gene family can be divided into two types: intron rich and no intron. Many stress-related elements were found in the 2000 bp upstream of the promoter, and PlantCARE predicted that CsCBL4 contained 30 stress-related elements. PlantPAN2 shows that CsCIPK6 contains 48 ABRELATERD1; CsCIPK17 contains 37 GT1CONSENSUS; CsCIPK3 contains 64 MYBCOREATCYCB1; CsCBL3 contains 52 SORLIP1AT; CsCBL5 contains 65 SURECOREATSULTR11; and CsCIPK11 contains 83 WBOXATNPR1. In addition, eight genes were selected for quantitative real-time PCR (RT-qPCR) to detect their expression profiles under high-temperature, low-temperature, salt, and drought treatments. These genes were found to be responsive to one or more abiotic stress treatments. The expression levels of CsCBL4, CsCIPK2, and CsCIPK14 were similar, and they were homologous to AtSOS3 and AtSIP3 and AtSIP4 in Arabidopsis, which were involved in the SOS pathway. This study provides insight into the potential functions of the CsCBL and CsCIPK of tea plant.


Assuntos
Camellia sinensis/genética , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas/genética , Proteínas Serina-Treonina Quinases/genética , Motivos de Aminoácidos , Sequência de Aminoácidos , Arabidopsis/genética , Proteínas de Ligação ao Cálcio/genética , Camellia sinensis/fisiologia , Sequência Conservada , Secas , Evolução Molecular , Redes Reguladoras de Genes , Estudo de Associação Genômica Ampla , Anotação de Sequência Molecular , Filogenia , Proteínas de Plantas/metabolismo , Estresse Fisiológico/genética
6.
BMC Evol Biol ; 19(1): 141, 2019 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-31296160

RESUMO

BACKGROUND: The LysM receptor-like kinases (LysM-RLKs) are important to both plant defense and symbiosis. Previous studies described three clades of LysM-RLKs: LysM-I/LYKs (10+ exons per gene and containing conserved kinase residues), LysM-II/LYRs (1-5 exons per gene, lacking conserved kinase residues), and LysM-III (two exons per gene, with a kinase unlike other LysM-RLK kinases and restricted to legumes). LysM-II gene products are presumably not functional as conventional receptor kinases, but several are known to operate in complexes with other LysM-RLKs. One aim of our study was to take advantage of recently mapped wild tomato transcriptomes to evaluate the evolutionary history of LysM-RLKs within and between species. The second aim was to place these results into a broader phylogenetic context by integrating them into a sequence analysis of LysM-RLKs from other functionally well-characterized model plant species. Furthermore, we sought to assess whether the Group III LysM-RLKs were restricted to the legumes or found more broadly across Angiosperms. RESULTS: Purifying selection was found to be the prevailing form of natural selection within species at LysM-RLKs. No signatures of balancing selection were found in species-wide samples of two wild tomato species. Most genes showed a greater extent of purifying selection in their intracellular domains, with the exception of SlLYK3 which showed strong purifying selection in both the extracellular and intracellular domains in wild tomato species. The phylogenetic analysis did not reveal a clustering of microbe/functional specificity to groups of closely related proteins. We also discovered new putative LysM-III genes in a range of Rosid species, including Eucalyptus grandis. CONCLUSIONS: The LysM-III genes likely originated before the divergence of E. grandis from other Rosids via a fusion of a Group II LysM triplet and a kinase from another RLK family. SlLYK3 emerges as an especially interesting candidate for further study due to the high protein sequence conservation within species, its position in a clade of LysM-RLKs with distinct LysM domains, and its close evolutionary relationship with LYK3 from Arabidopsis thaliana.


Assuntos
Evolução Molecular , Lycopersicon esculentum/enzimologia , Lycopersicon esculentum/genética , Proteínas Serina-Treonina Quinases/genética , Sequência de Aminoácidos , Filogenia , Domínios Proteicos , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Seleção Genética , Transcriptoma
7.
Exp Parasitol ; 204: 107727, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31344389

RESUMO

BACKGROUND: Trypanosoma rangeli is a protozoan parasite that is non-virulent to the mammalian host and is morphologically and genomically related to Trypanosoma cruzi, whose proliferation within the mammalian host is controversially discussed. OBJECTIVES: We aimed to investigate the T. rangeli cell cycle in vitro and in vivo by characterizing the timespan of the parasite life cycle and by proposing a molecular marker to assess cytokinesis. METHODOLOGY: The morphological events and their timing during the cell cycle of T. rangeli epimastigotes were assessed using DNA staining, flagellum labelling and bromodeoxyuridine incorporation. Messenger RNA levels of four genes previously associated with the cell cycle of trypanosomatids (AUK1, PLK, MOB1 and TRACK) were evaluated in the different T. rangeli forms. FINDINGS: T. rangeli epimastigotes completed the cell cycle in vitro in 20.8 h. PLK emerged as a potential molecular marker for cell division, as its mRNA levels were significantly increased in exponentially growing epimastigotes compared with growth-arrested parasites or in vitro-differentiated trypomastigotes. PLK expression in T. rangeli can be detected near the flagellum protrusion site, reinforcing its role in the cell cycle. Interestingly, T. rangeli bloodstream trypomastigotes exhibited very low mRNA levels of PLK and were almost entirely composed of parasites in G1 phase. MAIN CONCLUSIONS: Our work is the first to describe the T. rangeli cell cycle in vitro and proposes that PLK mRNA levels could be a useful tool to investigate the T. rangeli ability to proliferate within the mammalian host bloodstream.


Assuntos
Proteínas de Ciclo Celular/genética , Ciclo Celular/genética , Citocinese/fisiologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , RNA Mensageiro/análise , Trypanosoma rangeli/citologia , Animais , Bromodesoxiuridina/metabolismo , Ciclo Celular/efeitos dos fármacos , Citocinese/genética , DNA de Protozoário/química , DNA de Protozoário/isolamento & purificação , Citometria de Fluxo , Imunofluorescência , Hidroxiureia/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Inibidores da Síntese de Ácido Nucleico/farmacologia , RNA de Protozoário/genética , RNA de Protozoário/isolamento & purificação , Fatores de Tempo , Trypanosoma rangeli/efeitos dos fármacos , Trypanosoma rangeli/enzimologia , Trypanosoma rangeli/genética , Tripanossomíase/parasitologia
8.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(7): 704-707, 2019 Jul 10.
Artigo em Chinês | MEDLINE | ID: mdl-31302916

RESUMO

OBJECTIVE: To explore the genetic basis of a child featuring intellectual disability, developmental delay and epilepsy. METHODS: Cytogenetic and molecular analysis including chromosomal karyotyping analysis, single nucleotide polymorphism array (SNP array) and qPCR were performed. RESULTS: The karyotype of the child was determined as 46, XX; SNP array: arr [19]21q22.12q22.13(36 860 195-38 801 482)×1 dn. A heterozygous 1.9 Mb microdeletion was detected at 21q22.12q22.13. qPCR has confirmed deletion of exon 1 of the DYRK1A gene, which has occurred de novo. CONCLUSION: A 21q22 deletion was diagnosed with multiple genetic methods. Genotype-phenotype correlation suggested DYRK1A to be a candidate for intellectual disability.


Assuntos
Deficiências do Desenvolvimento/genética , Epilepsia/genética , Deficiência Intelectual/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética , Deleção de Sequência , Criança , Estudos de Associação Genética , Humanos , Cariotipagem
9.
Nat Commun ; 10(1): 2378, 2019 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-31147541

RESUMO

Developmental plasticity of root system architecture is crucial for plant performance in nutrient-poor soils. Roots of plants grown under mild nitrogen (N) deficiency show a foraging response characterized by increased root length but mechanisms underlying this developmental plasticity are still elusive. By employing natural variation in Arabidopsis accessions, we show that the brassinosteroid (BR) signaling kinase BSK3 modulates root elongation under mild N deficiency. In particular, a proline to leucine substitution in the predicted kinase domain of BSK3 enhances BR sensitivity and signaling to increase the extent of root elongation. We further show that low N specifically upregulates transcript levels of the BR co-receptor BAK1 to activate BR signaling and stimulate root elongation. Altogether, our results uncover a role of BR signaling in root elongation under low N. The BSK3 alleles identified here provide targets for improving root growth of crops growing under limited N conditions.


Assuntos
Proteínas de Arabidopsis/genética , Nitrogênio/deficiência , Raízes de Plantas/crescimento & desenvolvimento , Proteínas Serina-Treonina Quinases/genética , Arabidopsis , Proteínas de Arabidopsis/metabolismo , Brassinosteroides/metabolismo , Regulação da Expressão Gênica de Plantas , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Solo/química , Regulação para Cima
10.
Anticancer Res ; 39(6): 2689-2697, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31177103

RESUMO

Colorectal cancer (CRC) is the second most prevalent type of cancer among males and the third among females. CRC recurrence and poor prognosis may be related to the prevalence of chemotherapy-resistant cancer stem cells (CSCs). Recent studies have indicated the role of doublecortin-like kinase 1 (DCLK1) protein as a marker of CSC in CRC. This review focuses on the role of DCLK1 in CRC. Long-lived DCLK1-positive tuft cells can function as cancer-initiating cells. Numerous studies have shown DCLK1 overexpression to be significantly correlated with the stage of disease, the presence of metastasis and poor survival rate. DCLK1 may also be used to identify patients at high risk and those with chemotherapy-resistant tumors. DCLK1-specific drugs are examined as potential cancer treatments.


Assuntos
Neoplasias Colorretais/patologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Regulação para Cima , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Metástase Neoplásica , Estadiamento de Neoplasias , Células-Tronco Neoplásicas/metabolismo , Prognóstico , Análise de Sobrevida
11.
Life Sci ; 229: 277-287, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31150687

RESUMO

AIMS: Secreted protein acidic and rich in cysteine, (SPARC), is a matricellular protein implicated in the modulation of the extracellular matrix (ECM) and mitochondrial proteins expression. MAIN METHODS: To study the mechanism through which SPARC is involved in the possible link between ECM and mitochondria, C2C12 myoblasts were cultured with/without the exogenous addition/inhibition of SPARC as well as activation/inhibition of adenosine monophosphate-activated protein kinase (AMPK). Electrical pulse stimulation (EPS), was applied for 2 days in myotubes. KEY FINDINGS: The expressions of ECM-related (integrin-linked kinase (ILK), glycogen synthase kinase-3 beta (GSK-3ß), phosphorylated-GSK-3ß (p-GSK-3ß) and collagen 1a1), mitochondrial-related (AMPK, phosphorylated-AMPK (p-AMPK), succinate dehydrogenase (SDHB) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc1α)) and SPARC proteins and/or genes were measured after modulation of SPARC and/or AMPK as well as with or without EPS. The addition of SPARC in C2C12 myoblast increased the expression of ILK, p-GSK-3ß and p-AMPK whereas anti-SPARC antibody decreased them at different incubation times (0, 10, and 30 min, and 6 h). The AMPK activation increased SPARC, collagen 1a1, p-AMPK and SDHB proteins level, however, AMPK inhibition blunted the effects. EPS induced Sparc and Pgc1a genes expression. SIGNIFICANCE: Sparc, an EPS-induced gene, may be involved in the link between ECM remodeling and mitochondrial function in muscle via its interaction with ILK/AMPK.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Matriz Extracelular/metabolismo , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Mioblastos/metabolismo , Osteonectina/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Animais , Células Cultivadas , Estimulação Elétrica , Regulação da Expressão Gênica , Camundongos , Mitocôndrias/genética , Proteínas Mitocondriais/genética , Mioblastos/citologia , Osteonectina/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Fosforilação , Proteínas Serina-Treonina Quinases/genética
12.
Gene ; 710: 210-217, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31176733

RESUMO

Low temperature is a key stress factor for the growth and development of wheat (Triticum aestivum L.), and glycometabolism plays an important role in plant cold tolerance. Our previous study identified trehalose 6-phosphate synthase 11 gene (TaTPS11), which had a significantly different expression pattern between a high freezing-tolerant wheat cultivar and a low freezing-tolerant wheat cultivar. In this study, TaTPS11 was isolated from a winter-hardy wheat cultivar (D1) and overexpressed in Arabidopsis thaliana to study its effect on cold tolerance in plants. Transgenic plants expressing TaTPS11 had lower sucrose content, higher starch content, and higher activity of key enzyme (sucrose phosphate synthase, sucrose synthase, and invertase) involved in sucrose metabolism. In addition, the expression level of sucrose non-fermenting 1-related kinase 1 (SnRK1), which catalyzes the sucrose in plants, increased in the TaTPS11-overexpressed plants. These results indicated that heterologous expression of TaTPS11 influenced carbohydrate metabolism in Arabidopsis plants. The resultant plants had a significantly higher survival rate after -5 °C treatment for 2 h and exhibited enhanced cold tolerance without unfavorable phenotypes compared to wild-type. Our findings indicated that manipulation of TaTPS11 improved cold tolerance in plants and TaTPS11 had potential values in wheat cold-tolerance breeding.


Assuntos
Arabidopsis/genética , Resposta ao Choque Frio , Monoéster Fosfórico Hidrolases/genética , Triticum/enzimologia , Arabidopsis/crescimento & desenvolvimento , Arabidopsis/metabolismo , Metabolismo dos Carboidratos , Regulação da Expressão Gênica de Plantas , Monoéster Fosfórico Hidrolases/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Plantas Geneticamente Modificadas/crescimento & desenvolvimento , Proteínas Serina-Treonina Quinases/genética , Reação em Cadeia da Polimerase em Tempo Real , Sacarose/metabolismo , Triticum/genética
13.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(3): 833-838, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31204940

RESUMO

OBJECTIVE: To explore the expression level of PLK1 in mantle cell lymphoma(MCL), and the effect of silencing PLK1 gene by RNA interference on the cell proliferation, apoptosis, and cell cycle. METHODS: S-P immunohistochemistry technique was used to detect the expression of PLK1 in tissues of 42 patients with MCL and 30 patients with reactive proliferative lymphodenitis(RPL), their expression levels were compared and analyzed. The Jeko-1 cells were transfected with lentivirus contaiming PLK-1 shRNA, then the mRNA and protein expression of PLK-1 was detected by real-time guantitative PCR and Western blot nespectively, and the silencing efficacy of PLK-1 shRNA was identificd. The cell proliferation was detected by CCK method, the cell apoptosis was detected by Annexin V/PI double staining, the cell cycle was detected by PI single staining, the changes of apoptosis-related proteins BAX, BCL-2 and Caspase 3 were detected by Western blot. RESULTS: The positive expression rate of PLK-1 in tissue of MCL patients was 66.67%(28/42), which was significanfly higher than 20%(6/30) in tissue of RPL patients (P<0.05). The PLK-1 positive expression correlated with B symptom, IPI score, Ann-Arbor stage(P<0.05). After infection of Jeko-1 cells with lentivirus containing PLK-1 shRNA for 72 hours, the mRNA and protein expressions of PLK-1 were significantly down-regulated(P<0.05), the proliferation rate of cells in group of PLK-1 shRNA was significanly lower than that in control and Neg shRNA groups(P<0.05); the apoptosis rate of cells in PLK-1 shRNA group was (27.42±3.44)%, which was significantly higher than that in control group (1.23±0.42)% and Neg shRNA group (2.07±0.58) % (P<0.05). The cell cycle analysis showed that the cell ratio in G2/M phase of PLK-1 shRNA group was (27.21±3.59) %, which was higher than that in control group (13.28±2.63)% and Neg shRNA group (14.34±2.37) %. The detection of apoptosis-related proteins showed that the expression of BAX was up-regulated, the expression of BCL-2 was down-regnlated and the expression of caspase 3 was up-regulated. CONCLUSION: The PLK-l overexpression appears in tissue of MCL patients. The silencing PLK-1 gene can inhibit the proliferation of Jeko-1 cells, induce the apopotosis of Jeko-1 cells and arrestes cell cycle in G2/M phase.


Assuntos
Proteínas de Ciclo Celular/genética , Linfoma de Célula do Manto , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Linfoma de Célula do Manto/genética , RNA Interferente Pequeno
14.
Yonsei Med J ; 60(7): 659-666, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31250580

RESUMO

PURPOSE: To investigate associations for polymorphisms in ß-carotene 9',10'-oxygenase (BCO2, rs10431036 and rs11214109), proprotein convertase subtilisin kexin type 9 (PCSK9, rs11583680), and tribbles pseudokinase 1 (TRIB1, rs17321515 and rs2954029), as well as lifestyle factors, with ischemic stroke (IS). MATERIALS AND METHODS: This nested case-control study included 161 patients with IS and 483 matched control individuals. We collected medical reports, lifestyle details, and blood samples from individuals and used the PCR-ligase detection reaction method to genotype single nucleotide polymorphisms (SNPs). RESULTS: The GA+AA genotype of rs10431036 (p<0.001) and rs17321515 (p=0.003), the CT+TT genotype of rs11214109 (p=0.005), and the TA+AA genotype of rs2954029 (p=0.006) in dominant models increased the risk of IS. In additive models, the GG genotype of rs17321515 (p=0.005) and the TT genotype of rs2954029 (p=0.008) increased the risk of IS. Adequate intake of fruits/vegetables reduced the risk of IS (p=0.005). Although there was no interaction between genes and fruits/vegetables, people with inadequate intake of fruits/vegetables who carried a risk genotype had a higher risk of IS than those only having inadequate fruits/vegetables intake or those only carrying a risk genotype. Also, the haplotypes AC, AT, and GT (comprising rs10431036 and rs11214109) and GT (comprising rs2954029 and rs17321515) were found to be associated with an increased risk of IS (p<0.05). CONCLUSION: Polymorphisms in BCO2 and TRIB1 and fruits/vegetables intake were associated with IS. These results provide the theoretical basis for gene screening to prevent chronic cerebrovascular diseases.


Assuntos
Isquemia Encefálica/complicações , Dioxigenases/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Estilo de Vida , Polimorfismo de Nucleotídeo Único , Pró-Proteína Convertase 9/genética , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Acidente Vascular Cerebral/genética , Idoso , Estudos de Casos e Controles , Feminino , Frequência do Gene , Genótipo , Humanos , Pessoa de Meia-Idade , Proteínas Serina-Treonina Quinases/genética , Acidente Vascular Cerebral/complicações
15.
Nat Commun ; 10(1): 2655, 2019 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-31201320

RESUMO

CDKL5 deficiency disorder (CDD) is characterized by epilepsy, intellectual disability, and autistic features, and CDKL5-deficient mice exhibit a constellation of behavioral phenotypes reminiscent of the human disorder. We previously found that CDKL5 dysfunction in forebrain glutamatergic neurons results in deficits in learning and memory. However, the pathogenic origin of the autistic features of CDD remains unknown. Here, we find that selective loss of CDKL5 in GABAergic neurons leads to autistic-like phenotypes in mice accompanied by excessive glutamatergic transmission, hyperexcitability, and increased levels of postsynaptic NMDA receptors. Acute, low-dose inhibition of NMDAR signaling ameliorates autistic-like behaviors in GABAergic knockout mice, as well as a novel mouse model bearing a CDD-associated nonsense mutation, CDKL5 R59X, implicating the translational potential of this mechanism. Together, our findings suggest that enhanced NMDAR signaling and circuit hyperexcitability underlie autistic-like features in mouse models of CDD and provide a new therapeutic avenue to treat CDD-related symptoms.


Assuntos
Síndromes Epilépticas/patologia , Neurônios GABAérgicos/patologia , Proteínas Serina-Treonina Quinases/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Transdução de Sinais/genética , Espasmos Infantis/patologia , Animais , Comportamento Animal/efeitos dos fármacos , Códon sem Sentido , Modelos Animais de Doenças , Síndromes Epilépticas/tratamento farmacológico , Síndromes Epilépticas/genética , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Feminino , Humanos , Masculino , Memantina/farmacologia , Memantina/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Prosencéfalo/citologia , Prosencéfalo/efeitos dos fármacos , Prosencéfalo/patologia , Proteínas Serina-Treonina Quinases/deficiência , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Espasmos Infantis/tratamento farmacológico , Espasmos Infantis/genética , Resultado do Tratamento
16.
J Basic Microbiol ; 59(8): 834-845, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31210376

RESUMO

A bacterium's ability to thrive in the presence of multiple environmental stressors simultaneously determines its resilience. We showed that activation of the SigB-controlled general stress response by mild environmental or energy stress provided significant cross-protection to subsequent lethal oxidative, disulfide and nitrosative stress in Bacillus subtilis. SigB activation is mediated via the stressosome and RsbP, the main conduits of environmental and energy stress, respectively. Cells exposed to mild environmental stress while lacking the major stressosome components RsbT or RsbRA were highly sensitive to subsequent oxidative stress, whereas rsbRB, rsbRC, rsbRD, and ytvA null mutants showed a spectrum of sensitivity, confirming their redundant roles and suggesting they could modulate the signals generated by environmental or oxidative stress. By contrast, cells encountering stationary phase stress required RsbP but not RsbT to survive subsequent oxidative stress. Interestingly, optimum cross-protection against nitrosative stress caused by sodium nitropruside required SigB but not the known regulators, RsbT and RsbP, suggesting an additional and as yet uncharacterized route of SigB activation independent of the known regulators. Together, these results provide mechanistic information on how B. subtilis promotes enhanced resistance against lethal oxidative stress during mild environmental and energy stress conditions.


Assuntos
Bacillus subtilis/fisiologia , Proteínas de Bactérias/metabolismo , Estresse Oxidativo/fisiologia , Fosfoproteínas Fosfatases/metabolismo , Fator sigma/metabolismo , Transdução de Sinais , Bacillus subtilis/genética , Bacillus subtilis/metabolismo , Proteínas de Bactérias/genética , Deleção de Genes , Viabilidade Microbiana , Estresse Nitrosativo/fisiologia , Fosfoproteínas Fosfatases/genética , Fosfoproteínas/genética , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Fator sigma/genética , Transdução de Sinais/genética
17.
Med Oncol ; 36(8): 70, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31203460

RESUMO

Alterations in BRCA2, PALB2, CHEK2, and p53 genes have been identified for their association with male breast cancer in various studies. The incidence of male breast cancer in India is consistent with its global rate. The present study was carried out with an aim to evaluate the genetic alterations in male breast cancer patients from Malwa region of Punjab, India. Four male breast cancer patients belonging to different families were recruited from Guru Gobind Singh Medical College and Hospital, Faridkot, India. A total of 51 genes reported with implications in the pathogenesis of breast cancer were screened using next generation sequencing. Germline variations were found in BRCA1, BRCA2, PMS2, p53, and PALB2 genes, previously reported to be associated with MBC as well as FBC. In addition to these, 13 novel missense alterations were detected in eight genes including STK11, FZR1, PALB2, BRCA2, NF2, BAP1, BARD1, and CHEK2. Impact of these missense alterations on structure and function of protein was also analyzed through molecular dynamics simulation. Structural analysis of these single nucleotide polymorphisms (SNPs) revealed significant impact on the encoded protein functioning.


Assuntos
Neoplasias da Mama Masculina/genética , Idoso , Proteína BRCA2/genética , Neoplasias da Mama Masculina/epidemiologia , Quinase do Ponto de Checagem 2/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Humanos , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Simulação de Dinâmica Molecular , Mutação , Linhagem , Polimorfismo de Nucleotídeo Único , Proteínas Serina-Treonina Quinases/genética , Proteína Supressora de Tumor p53/genética , Ubiquitina-Proteína Ligases/genética
18.
Zhonghua Gan Zang Bing Za Zhi ; 27(4): 281-285, 2019 Apr 20.
Artigo em Chinês | MEDLINE | ID: mdl-31082339

RESUMO

Objective: To construct and screen optimal siRNA interference sequence of CIT gene and to detect its interference efficiency as well as proliferation effect in human hepatoma cell line SK-Hep-1. Methods: Three siRNA target spots were designed and synthesized according to the CIT gene sequence. SK-Hep-1 HCC cells were transfected by liposome transfection. The knockdown efficiency of the target CIT gene was detected by real-time PCR and Western blot. Expressional change of CIT in SK-Hep-1 cells after 48 hours of siRNA interference were observed by immunohistochemistry and confocal microscopy. The proliferation of SK-Hep-1 cells after 48 hours of siRNA interference was detected by EdU cell proliferation assay. A t-test was used to compare the mean of two samples, and one-way ANOVA was used to compare the mean of multiple samples. Results: Western blot results showed that the three interference sequences were targeted at different target spots. The expression level of CIT protein in KD-1,-2, and-3 groups were decreased (P < 0.01) than control, while the protein expression level of KD1 group was the lowest. Real-time PCR results showed that compared with the control group, the expression level of CIT mRNA in KD-1, -2, and -3 groups decreased (P < 0.01), while that in KD1 group was the lowest. Laser confocal microscopy also confirmed that the morphological expression of CIT attenuated significantly after transfection with siRNA. The results of EdU proliferation assay showed that siRNA transfected with CIT significantly attenuated the proliferation of SK-Hep-1 hepatoma cells (P < 0.05). Conclusion: The successful construction and screening of siRNA fragments can effectively inhibit the expression and proliferation of CIT gene in hepatoma SK-Hep-1.


Assuntos
Carcinoma Hepatocelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Neoplasias Hepáticas/genética , Proteínas Serina-Treonina Quinases/genética , RNA Interferente Pequeno/genética , Proteínas Sanguíneas , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Neoplasias Hepáticas/patologia , Interferência de RNA , RNA Mensageiro/genética , Transfecção
19.
Nat Commun ; 10(1): 2148, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31089135

RESUMO

Mechanisms of lung squamous cell carcinoma (LSCC) development are poorly understood. Here, we report that JNK1/2 activities attenuate Lkb1-deficiency-driven LSCC initiation and progression through repressing ΔNp63 signaling. In vivo Lkb1 ablation alone is sufficient to induce LSCC development by reducing MKK7 levels and JNK1/2 activities, independent of the AMPKα and mTOR pathways. JNK1/2 activities is positively regulated by MKK7 during LSCC development. Pharmaceutically elevated JNK1/2 activities abates Lkb1 dependent LSCC formation while compound mutations of Jnk1/2 and Lkb1 further accelerate LSCC progression. JNK1/2 is inactivated in a substantial proportion of human LSCC and JNK1/2 activities positively correlates with survival rates of lung, cervical and head and neck squamous cell carcinoma patients. These findings not only determine a suppressive role of the stress response regulators JNK1/2 on LSCC development by acting downstream of the key LSCC suppresser Lkb1, but also demonstrate activating JNK1/2 activities as a therapeutic approach against LSCC.


Assuntos
Carcinoma de Células Escamosas/patologia , Neoplasias Pulmonares/patologia , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Proteína Quinase 9 Ativada por Mitógeno/metabolismo , Proteínas Serina-Treonina Quinases/deficiência , Idoso , Idoso de 80 Anos ou mais , Animais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/mortalidade , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , MAP Quinase Quinase 7/metabolismo , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Proteína Quinase 8 Ativada por Mitógeno/genética , Proteína Quinase 9 Ativada por Mitógeno/genética , Proteínas Serina-Treonina Quinases/genética , Taxa de Sobrevida , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo
20.
Life Sci ; 228: 221-227, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31075231

RESUMO

AIMS: MicroRNAs (miRNAs) are small noncoding RNAs that negatively control gene expression at the translational level. There are compelling evidences indicating that the expression of let-7e is downregulated in various cancers, however, the role of let-7e in colorectal cancer (CRC) and its mechanism has been remained unknown. Here, we investigated the potential role of let-7e in regulating CRC cells phenotypes. MAIN METHODS: Let-7e and DCLK1 siRNA were transfected in HCT-116 cells. Colony formation assay, scratch test, Annexin V/PI flow cytometry, and sphere formation assay were performed to examine the cell proliferation, migration, apoptosis, and stemness, respectively. The expression of let-7e, epithelial-mesenchymal transition (EMT)-related genes, Doublecortin like kinase protein 1 (DCLK1), and cancer stem cells (CSCs) were assessed using RT-qPCR while the protein level of DCLK1 was determined by western blotting. KEY FINDINGS: Overexpression of let-7e effectively inhibited cell proliferation, suppressed migration, reduced sphere formation, and precluded EMT process as well as stemness factors. Furthermore, let-7e suppressed DCLK1 expression. Additionally, we found that the expression of let-7e was negatively correlated with DCLK1 expression in CRC cells. SIGNIFICANCE: Let-7e plays an important role as tumor suppressor miRNA in CRC probably through inhibition of DCLK1 expression.


Assuntos
Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intracelular/genética , MicroRNAs/genética , Proteínas Serina-Treonina Quinases/genética , Carcinogênese/genética , Carcinogênese/patologia , Proliferação de Células , Neoplasias Colorretais/patologia , Regulação para Baixo , Transição Epitelial-Mesenquimal , Células HCT116 , Humanos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA