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1.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 41(5): 601-608, 2019 Oct 30.
Artigo em Chinês | MEDLINE | ID: mdl-31699189

RESUMO

Objective To investigate the expression and clinical significance of late endosomal/lysosomal adaptor,mitogen-activated protein kinase and mammalian target of rapamycin activator 3(LAMTOR3)in bladder carcinoma.Methods Oncomine and Expression Atlas were used to extract the useful mining gene chip database for analyzing the expression of LAMTOR3 in bladder carcinoma tissues and cell lines,and the correlation of LAMTOR3 with the clinicopathological features were analyzed.RT-PCR,Western blot,and immunohistochemistry were performed to detect the expression of LAMTOR3 in bladder carcinoma cell lines,specimens,and adjacent normal tissues for verifying the results exploited from the above databases.Results The Expression Atlas showed that LAMTOR3 had high expressions in Hs172.T,HT-1376,RT4,JMSU-1,and T24 cell lines among 20 bladder carcinoma cell lines,among which the LAMTOR3 expression was different.Oncomine reported that LAMTOR3 expression in bladder carcinoma,including invasive(t=2.857,P=0.005)and non-invasive carcinoma(t=3.105,P=0.003),was significantly higher than that in adjacent normal tissues.The expression of LAMTOR3 was positively correlated with pathological grade(P<0.05).The expressions of LAMTOR3 mRNA in bladder carcinoma cell lines,including UMUC3(t=10.84,P=0.0084),J82(t=21.75,P=0.0021),5637(t=45.88,P=0.0005),and T24(t=87.58,P=0.0001)were significantly higher than that in normal bladder cell line SV-HUC-1,while its expression in bladder carcinoma tissues was significantly higher than that in adjacent normal tissues(P<0.05),so was its protein level in tissues(P<0.05).Immunohistochemistry showed that LAMTOR3 protein was over-expressed in bladder carcinoma tissues;its level in invasive carcinoma tissues was higher than that in no-invasive carcinoma tissues and was related closely with the clinical stages(χ 2=9.189,P=0.002),pathological grades(χ 2=4.746,P=0.029),and lymphatic metastasis(χ 2=6.210,P=0.013)but had no significant correlation to sex(χ 2=0.965,P=0.326),age(χ 2=2.126,P=0.145),and distant metastasis(χ 2=1.261,P=0.261).Conclusion LAMTOR3 is highly expressed in bladder carcinoma cell lines and tissues and plays a key role in the development and progression of bladder carcinoma.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasias da Bexiga Urinária/genética , Linhagem Celular Tumoral , Humanos , Prognóstico , Neoplasias da Bexiga Urinária/patologia
2.
J Environ Pathol Toxicol Oncol ; 38(3): 195-203, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31679307

RESUMO

UNCI 19 expression has been reported to be significantly higher in hepatic cancer cells (HCC). However, the clinical significance of modulating UNC119 expression in HCC is not well understood. The study described here aimed to explore the potential of curcumin in modulation of UNC119 expression in HCC by assessment with quantitative real-time PCR, western blot, and immune-histochemical analyses in HCC cell lines and tissues. The biological functions of UNC119 in the proliferation, growth, and cycle of tumor cells were analyzed both in vitro and in vivo. UNC119 expression was upregulated in HCC cell lines and tissues as indicated by comparison with normal liver cells and tissues. Cellular function assays showed that higher levels of UNC119 not only promoted proliferation but also enhanced HCC cell migration and invasion. UNC119 promoted progression of the cell cycle and significantly promoted HCC cell growth through the Wnt/ß-catenin signal pathway, and enhanced tumor migration and invasion by the TGF-ß/EMT pathway. Curcumin efficiently inhibited HCC cell proliferation by blocking the Wnt/ß-catenin pathway and inhabited migration and invasion by blocking the TGF-p/EMT signal pathway. Curcumin not only was beneficial for tumor remission but also contributed to the long-term survival of HCC-bearing mice. UNC119 was significantly upregulated and promoted cell growth in hepatic cancer cells and tissues by the Wnt/ß-catenin signal pathway and migration by TGF-ß/EMT signal pathway. Curcumin treatment inhibited cell proliferation, growth, migration, and invasion by inhibition of those pathways.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Curcumina/farmacologia , Invasividade Neoplásica/genética , Metástase Neoplásica/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Feminino , Células Hep G2 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Organismos Livres de Patógenos Específicos
3.
JAMA ; 322(17): 1682-1691, 2019 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-31688885

RESUMO

Importance: Primary open-angle glaucoma presents with increased prevalence and a higher degree of clinical severity in populations of African ancestry compared with European or Asian ancestry. Despite this, individuals of African ancestry remain understudied in genomic research for blinding disorders. Objectives: To perform a genome-wide association study (GWAS) of African ancestry populations and evaluate potential mechanisms of pathogenesis for loci associated with primary open-angle glaucoma. Design, Settings, and Participants: A 2-stage GWAS with a discovery data set of 2320 individuals with primary open-angle glaucoma and 2121 control individuals without primary open-angle glaucoma. The validation stage included an additional 6937 affected individuals and 14 917 unaffected individuals using multicenter clinic- and population-based participant recruitment approaches. Study participants were recruited from Ghana, Nigeria, South Africa, the United States, Tanzania, Britain, Cameroon, Saudi Arabia, Brazil, the Democratic Republic of the Congo, Morocco, Peru, and Mali from 2003 to 2018. Individuals with primary open-angle glaucoma had open iridocorneal angles and displayed glaucomatous optic neuropathy with visual field defects. Elevated intraocular pressure was not included in the case definition. Control individuals had no elevated intraocular pressure and no signs of glaucoma. Exposures: Genetic variants associated with primary open-angle glaucoma. Main Outcomes and Measures: Presence of primary open-angle glaucoma. Genome-wide significance was defined as P < 5 × 10-8 in the discovery stage and in the meta-analysis of combined discovery and validation data. Results: A total of 2320 individuals with primary open-angle glaucoma (mean [interquartile range] age, 64.6 [56-74] years; 1055 [45.5%] women) and 2121 individuals without primary open-angle glaucoma (mean [interquartile range] age, 63.4 [55-71] years; 1025 [48.3%] women) were included in the discovery GWAS. The GWAS discovery meta-analysis demonstrated association of variants at amyloid-ß A4 precursor protein-binding family B member 2 (APBB2; chromosome 4, rs59892895T>C) with primary open-angle glaucoma (odds ratio [OR], 1.32 [95% CI, 1.20-1.46]; P = 2 × 10-8). The association was validated in an analysis of an additional 6937 affected individuals and 14 917 unaffected individuals (OR, 1.15 [95% CI, 1.09-1.21]; P < .001). Each copy of the rs59892895*C risk allele was associated with increased risk of primary open-angle glaucoma when all data were included in a meta-analysis (OR, 1.19 [95% CI, 1.14-1.25]; P = 4 × 10-13). The rs59892895*C risk allele was present at appreciable frequency only in African ancestry populations. In contrast, the rs59892895*C risk allele had a frequency of less than 0.1% in individuals of European or Asian ancestry. Conclusions and Relevance: In this genome-wide association study, variants at the APBB2 locus demonstrated differential association with primary open-angle glaucoma by ancestry. If validated in additional populations this finding may have implications for risk assessment and therapeutic strategies.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Grupo com Ancestrais do Continente Africano/genética , Estudo de Associação Genômica Ampla , Glaucoma de Ângulo Aberto/etnologia , Glaucoma de Ângulo Aberto/genética , Polimorfismo de Nucleotídeo Único , Idoso , Peptídeos beta-Amiloides/genética , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Imuno-Histoquímica , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Fatores de Risco
4.
Medicine (Baltimore) ; 98(44): e17749, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31689829

RESUMO

RATIONALE: Early infantile epileptic encephalopathy (EIEE) 65 was recently shown to be caused by the cytoplasmic FMRP interacting protein 2 (CYFIP2) mutation. To date, only 5 cases have been reported in two articles, and all the outcomes in all cases were poor. PATIENT CONCERNS: In this study, we reported an 8-month-old girl with a 1 month-long history of seizures and developmental delay. Over 1 month later, she developed epileptic spasms in clusters with hypsarrhythmia on electroencephalography. DIAGNOSIS: The patient was diagnosed with EIEE 65 and trio-based whole-exome sequencing revealed a causative de novo CYFIP2 mutation c.260G >T (p.Arg87Leu). INTERVENTIONS: The proband was successively treated with multiple antiepileptic drugs, including levetiracetam, phenobarbital, VitB6, topiramate, methylprednisolone, prednisone, valproic acid and vigabatrin. OUTCOMES: After resistance to multiple anti-epileptic drugs over 2 months of treatment, she finally achieved seizure-free several days after vigabatrin administration and her developmental delay steadily improved. LESSONS: OUR: case confirmed that CYFIP2 was the pathogenic gene of EIEE 65. We also first demonstrated vigabatrin might be effective for control of seizures and helpful for the improved outcomes of these patients.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Mutação/genética , Espasmos Infantis/genética , Anticonvulsivantes/uso terapêutico , Diagnóstico Precoce , Feminino , Humanos , Lactente , Espasmos Infantis/diagnóstico , Espasmos Infantis/tratamento farmacológico , Resultado do Tratamento
6.
Forensic Sci Int ; 302: 109906, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31419596

RESUMO

The aim of this study is to determine the molecular mechanism of sudden death in a previously healthy patient. Clinical exome sequencing revealed I536T-RBM20 variant, which alters RNA splicing of TTN and is causative for dilated cardiomyopathy. Comprehensive RNA sequencing (RNA-seq) was also performed in the patient samples and the control samples. Splicing abnormality was compared in cardiac muscle and skeletal muscle. RNA-seq analysis of the cardiac and skeletal muscle showed abnormal splicing of LDB3, not of TTN. Exon 11 of LDB3 was abnormally included in the patient samples compared with the control samples. This abnormal LDB3 splicing pattern in skeletal muscle has been reported in myotonic dystrophy type 1 (DM1) patients. We, thus, confirmed that the patient had expanded CTG repeat in DMPK and the diagnosis was genetically DM1. This finding suggest that one of the molecular mechanisms of sudden cardiac death in this asymptomatic subclinical DM1 patient might be LDB3 abnormal splicing due to the CTG repeat in DMPK, rather than RBM20 variant. RNA-seq analysis is useful to determine the exact molecular diagnosis for sudden cardiac death.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Morte Súbita Cardíaca/etiologia , Proteínas com Domínio LIM/genética , Distrofia Miotônica/diagnóstico , Processamento de RNA , Doenças Assintomáticas , Éxons , Humanos , Masculino , Miotonina Proteína Quinase/genética , Análise de Sequência de RNA , Expansão das Repetições de Trinucleotídeos , Adulto Jovem
7.
Life Sci ; 234: 116788, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31445935

RESUMO

Livin is an important member of the human inhibitor of apoptosis proteins (IAPs) family. IAPs are proteins with antiapoptotic abilities, and their functions are different from the Bcl-2 (B-cell lymphoma-2) family proteins. However, the precise role of Livin in colon cancer progression remains unclear. The purpose of this study is to assess the effect of overexpression Livin in colon cancer cells and to examine its molecular mechanism. We demonstrated that Livin induced a colon cancer phenotype, including proliferation and migration, by regulating H2A.XY39ph (histone family 2A variant (H2AX) phosphorylated on the 39th serine site). We elucidated that Livin degraded Jumonji-C domain-containing 6 protein (JMJD6), which was mediated by the proteasome murine double minute 2 (MDM2), thereby regulating H2A.XY39ph. Above all, the overexpression of JMJD6 recovered H2A.XY39ph in colon cancer cells with a high level of Livin, thus inhibiting colon cancer malignancy progression. These results reveal a previously unrecognized role for Livin in regulating the tumor-initiating capacity in colon cancer and provide a novel treatment strategy in cancer via the interruption of H2A.XY39ph function and the interaction between H2A.XY39ph and JMJD6.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias do Colo/patologia , Histonas/metabolismo , Proteínas Inibidoras de Apoptose/metabolismo , Histona Desmetilases com o Domínio Jumonji/metabolismo , Proteínas de Neoplasias/metabolismo , Mapas de Interação de Proteínas , Proteínas Adaptadoras de Transdução de Sinal/genética , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Histonas/genética , Humanos , Proteínas Inibidoras de Apoptose/genética , Histona Desmetilases com o Domínio Jumonji/genética , Proteínas de Neoplasias/genética , Proteólise
8.
Int Heart J ; 60(5): 1083-1090, 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31447468

RESUMO

Contemporary studies have identified rs10494366 in the nitric oxide synthase 1 adaptor protein (NOS1AP) gene as a new genetic marker in modulating the QT interval and sudden cardiac death (SCD) in general populations. However, the conclusions were not coincident. Therefore, we conducted for the first time a system evaluation of the relativity of rs10494366, the QT interval, and sudden death by meta-analysis. In our study, the meta-analysis displayed the GG genotype of rs10494366 correlated with the QT interval in women with no heterogeneity, and in diabetes mellitus (DM) patients with minor heterogeneity. In the Caucasian population, the correlation of rs10494366 and sudden death was significant. The heterogeneity referred to the relevance between rs10494366 and sudden death in the Asian population. In conclusion, the minor allele of rs10494366 may have an impact on the QT interval in women or DM patients and may have a potential role in sudden death in the Caucasian population.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Morte Súbita Cardíaca/epidemiologia , Predisposição Genética para Doença/epidemiologia , Síndrome do QT Longo/genética , Síndrome do QT Longo/mortalidade , Polimorfismo de Nucleotídeo Único/genética , Alelos , Grupo com Ancestrais do Continente Asiático/genética , China , Morte Súbita Cardíaca/etnologia , Eletrocardiografia , Feminino , Genótipo , Humanos , Masculino , Análise de Sobrevida
9.
Nucleic Acids Res ; 47(15): 7734-7752, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31350900

RESUMO

DAXX displays complex biological functions. Remarkably, DAXX overexpression is a common feature in diverse cancers, which correlates with tumorigenesis, disease progression and treatment resistance. Structurally, DAXX is modular with an N-terminal helical bundle, a docking site for many DAXX interactors (e.g. p53 and ATRX). DAXX's central region folds with the H3.3/H4 dimer, providing a H3.3-specific chaperoning function. DAXX has two functionally critical SUMO-interacting motifs. These modules are connected by disordered regions. DAXX's structural features provide a framework for deciphering how DAXX mechanistically imparts its functions and how its activity is regulated. DAXX modulates transcription through binding to transcription factors, epigenetic modifiers, and chromatin remodelers. DAXX's localization in the PML nuclear bodies also plays roles in transcriptional regulation. DAXX-regulated genes are likely important effectors of its biological functions. Deposition of H3.3 and its interactions with epigenetic modifiers are likely key events for DAXX to regulate transcription, DNA repair, and viral infection. Interactions between DAXX and its partners directly impact apoptosis and cell signaling. DAXX's activity is regulated by posttranslational modifications and ubiquitin-dependent degradation. Notably, the tumor suppressor SPOP promotes DAXX degradation in phase-separated droplets. We summarize here our current understanding of DAXX's complex functions with a focus on how it promotes oncogenesis.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/genética , Neoplasias/genética , Proteínas Nucleares/genética , Processamento de Proteína Pós-Traducional , Proteínas Adaptadoras de Transdução de Sinal/química , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Linhagem Celular Tumoral , Cromatina/química , Humanos , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Neoplasias/patologia , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Fosforilação , Ligação Proteica , Mapeamento de Interação de Proteínas , Transdução de Sinais , Sumoilação , Transcrição Genética , Ubiquitinação
10.
Cell Mol Life Sci ; 76(20): 4009-4021, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31270580

RESUMO

Imprinted genes display parent-of-origin-specific expression with this epigenetic system of regulation found exclusively in therian mammals. Historically, defined imprinted gene functions were almost solely focused on pregnancy and the influence on the growth parameters of the developing embryo and placenta. More recently, a number of postnatal functions have been identified which converge on resource allocation, both for animals in the nest and in adults. While many of the prenatal functions of imprinted genes that have so far been described adhere to the "parental conflict" hypothesis, no clear picture has yet emerged on the functional role of imprints on postnatal metabolism. As these roles are uncovered, interest in the potential for these genes to influence postnatal metabolism and associated adult-onset disease outcomes when dysregulated has gathered pace. Here, we review the published data on imprinted genes and their influence on postnatal metabolism, starting in the nest, and then progressing through to adulthood. When observing the functional effects of these genes on adult metabolism, we must always be careful to acknowledge the influence both of direct expression in the relevant metabolic tissue, but also indirect metabolic programming effects caused by their modulation of both in utero and postnatal growth trajectories.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Regulação da Expressão Gênica no Desenvolvimento , Impressão Genômica , Herança Materna , Herança Paterna , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Animais , Comportamento Animal , Regulação da Temperatura Corporal/genética , Embrião de Mamíferos , Desenvolvimento Embrionário , Feminino , Humanos , Masculino , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia , Placenta/metabolismo , Gravidez
11.
Cancer Sci ; 110(9): 2973-2981, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31293054

RESUMO

Every year, approximately 1.2 million cases of colorectal carcinoma (CRC) are newly diagnosed worldwide. Although metastases to distant organs are often fatal complications of CRC, little information is known as to how such metastatic lesions are formed. To reveal the genetic profiles for CRC metastasis, we conducted whole-exome RNA sequencing on CRC tumors with liver metastasis (LM) (group A, n = 12) and clinical stage-matched larger tumors without LM (group B, n = 16). While the somatic mutation profiles were similar among the primary tumors and LM lesions in group A and the tumors in group B, the A-to-C nucleotide change in the context of "AAG" was only enriched in the LM regions in group A, suggesting the presence of a DNA damage process specific to metastasis. Genes already known to be associated with CRC were mutated in all groups at a similar frequency, but we detected somatic nonsynonymous mutations in a total of 707 genes in the LM regions, but not in the tumors without LM. Signaling pathways linked to such "LM-associated" genes were overrepresented for extracellular matrix-receptor interaction or focal adhesion. Further, fusions of the ADAP1 (ArfGAP with dual PH domain 1) were newly identified in our cohort (3 out of 28 patients), which activated ARF6, an ADAP1-substrate. Infrequently, mutated genes may play an important role in metastasis formation of CRC. Additionally, recurrent ADAP1 fusion genes were unexpectedly discovered. As these fusions activate small GTPase, further experiments are warranted to examine their contribution to CRC carcinogenesis.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasias Colorretais/genética , Fusão Gênica , Neoplasias Hepáticas/genética , Proteínas do Tecido Nervoso/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinogênese/genética , Neoplasias Colorretais/patologia , Análise Mutacional de DNA , Feminino , Perfilação da Expressão Gênica , Células HEK293 , Humanos , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Mutação Puntual , Sequenciamento Completo do Exoma
12.
Nat Cell Biol ; 21(7): 889-899, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31263264

RESUMO

The c-Myc oncogene drives malignant progression and induces robust anabolic and proliferative programmes leading to intrinsic stress. The mechanisms enabling adaptation to MYC-induced stress are not fully understood. Here we reveal an essential role for activating transcription factor 4 (ATF4) in survival following MYC activation. MYC upregulates ATF4 by activating general control nonderepressible 2 (GCN2) kinase through uncharged transfer RNAs. Subsequently, ATF4 co-occupies promoter regions of over 30 MYC-target genes, primarily those regulating amino acid and protein synthesis, including eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), a negative regulator of translation. 4E-BP1 relieves MYC-induced proteotoxic stress and is essential to balance protein synthesis. 4E-BP1 activity is negatively regulated by mammalian target of rapamycin complex 1 (mTORC1)-dependent phosphorylation and inhibition of mTORC1 signalling rescues ATF4-deficient cells from MYC-induced endoplasmic reticulum stress. Acute deletion of ATF4 significantly delays MYC-driven tumour progression and increases survival in mouse models. Our results establish ATF4 as a cellular rheostat of MYC activity, which ensures that enhanced translation rates are compatible with survival and tumour progression.


Assuntos
Fator 4 Ativador da Transcrição/genética , Genes myc/genética , Ativação Transcricional/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Estresse do Retículo Endoplasmático/genética , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos Transgênicos , Fosfoproteínas/genética , Fosforilação , Biossíntese de Proteínas/fisiologia , Serina-Treonina Quinases TOR/metabolismo
13.
BMC Med Genet ; 20(1): 119, 2019 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-31272422

RESUMO

BACKGROUND: Mutations in ARL6IP1, which encodes a tetraspan membrane protein localized to the endoplasmic reticulum (ER), have been recently described in a large family with a complicated form of hereditary spastic paraplegia (HSP). CASE PRESENTATION: We sought to expand the HSP phenotype associated with ARL6IP1 variants by examining a Saudi kindred with a clinically more severe presentation, which resulted in spontaneous neonatal death of both affected siblings. Clinical features encompassed not only spastic paraplegia but also developmental delay, microcephaly, cerebral atrophy, periventricular leukoencephalopathy, hypotonia, seizures, spasticity, jejunal stricture, gastrointestinal reflux, neuropathy, dysmorphism and respiratory distress. We performed clinical assessment and radiological studies of this family, in addition to homozygosity mapping and whole exome sequencing (WES) to identify the disease-associated variant. Homozygosity mapping localized the causative gene to a region on chromosome 16 harboring ARL6IP1. WES of the index case identified the homoallelic nonsense variant, c.112C > T in ARL6IP1 that segregated with the phenotype and was predicted to result in loss of the protein. Allelic expression analysis of the parents demonstrated downward pressure on the mutant allele, suggestive of nonsense-mediated decay. CONCLUSIONS: Our report shows that the phenotype associated with ARL6IP1 variants may be broader and more acute than so far reported and identifies fatal HSP as the severe end of the phenotypic spectrum of ARL6IP1 variants.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Estudos de Associação Genética , Predisposição Genética para Doença/genética , Variação Genética , Proteínas de Membrana/genética , Mutação , Paraplegia Espástica Hereditária/genética , Alelos , Pré-Escolar , Retículo Endoplasmático/metabolismo , Feminino , Regulação da Expressão Gênica , Homozigoto , Humanos , Masculino , Mutação/genética , Linhagem , Fenótipo , Arábia Saudita , Paraplegia Espástica Hereditária/diagnóstico por imagem , Paraplegia Espástica Hereditária/fisiopatologia , Sequenciamento Completo do Exoma
14.
Nat Commun ; 10(1): 3055, 2019 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-31296870

RESUMO

KRAS mutations are present in over 90% of pancreatic ductal adenocarcinomas (PDAC), and drive their poor outcomes and failure to respond to targeted therapies. Here we show that Leukemia Inhibitory Factor (LIF) expression is induced specifically by oncogenic KRAS in PDAC and that LIF depletion by genetic means or by neutralizing antibodies prevents engraftment in pancreatic xenograft models. Moreover, LIF-neutralizing antibodies synergize with gemcitabine to eradicate established pancreatic tumors in a syngeneic, KrasG12D-driven, PDAC mouse model. The related cytokine IL-6 cannot substitute for LIF, suggesting that LIF mediates KRAS-driven malignancies through a non-STAT-signaling pathway. Unlike IL-6, LIF inhibits the activity of the Hippo-signaling pathway in PDACs. Depletion of YAP inhibits the function of LIF in human PDAC cells. Our data suggest a crucial role of LIF in KRAS-driven pancreatic cancer and that blockade of LIF by neutralizing antibodies represents an attractive approach to improving therapeutic outcomes.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Fator Inibidor de Leucemia/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Feminino , Técnicas de Inativação de Genes , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Fator Inibidor de Leucemia/antagonistas & inibidores , Fator Inibidor de Leucemia/genética , Camundongos , Mutação , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais/genética , Fatores de Transcrição , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Medicine (Baltimore) ; 98(28): e16414, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31305457

RESUMO

The gestational weight gain is determined by food habits, environmental and genetic factors.The aims of this paper were to establish relationships between maternal gene polymorphisms (patatin-like phospholipase domain-containing protein 3 rs738409 [PNPLA3 rs738409], glucokinase regulatory protein rs780094 [GCKR rs780094], and guanine nucleotide-binding protein rs5443 [GNB3 rs5443]) and mothers' gestational weight gain, but also neonatal outcomes (birth weight, length, and ponderal index [PI]).We performed a cross-sectional study in a sample of 158 mothers and their product of conception' in an Obstetrics-Gynecology Clinic from Romania. We divided the pregnant women according to the Institute of Medicine recommendations into 3 subgroups: (1) insufficient gestational weight gain; (2) normal gestational weight gain; and (3) excessive gestational weight gain.The gestational weight gain among pregnant women included in this study was classified as insufficient (10.1%), normal (31%), and excessive (58.9%). We found a tendency towards statistical significance for mothers that were overweight or obese before pregnancy to present an excessive gestational weight gain as compared to the normal weight ones. Similarly, we identified a tendency for statistical significance regarding the association between the variant genotype of GNB3 rs5443 and excessive gestational weight gain. We noticed differences that tended to be statistical significant concerning aspartate aminotransferase values between the 3 subgroups, mothers with excessive gestational weight gain having higher values than mothers with normal gestational weight gain (median, IQR: 22.89[17.53; 31.59] for mothers with excessive gestational weight gain versus 22.71[18.58; 27.37] for mothers with normal gestational weight gain). In mothers with excessive gestational weight gain, we found a significant association between the variant genotype of PNPLA3 rs738409 polymorphism and neonatal PI noticing a decrease of this index in case of newborns from mothers carrying the variant genotype.Excessive gestational weight gain was noticed in pregnant women that were obese and overweight before pregnancy. We found a positive association between the variant genotype of GNB3 rs5443 polymorphism and excessive gestational weight gain. Similarly, the presence of variant genotype of PNPLA3 rs738409 in mothers was associated with a lower PI in their newborns. Our study pointed out the most important factors that influence gestational weight gain and related birth outcomes.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Desenvolvimento Infantil , Ganho de Peso na Gestação/genética , Proteínas Heterotriméricas de Ligação ao GTP/genética , Lipase/genética , Proteínas de Membrana/genética , Adolescente , Adulto , Peso ao Nascer , Estatura , Estudos Transversais , Feminino , Estudos de Associação Genética , Humanos , Recém-Nascido , Sobrepeso/genética , Polimorfismo de Nucleotídeo Único , Gravidez , Complicações na Gravidez/epidemiologia , Complicações na Gravidez/genética , Adulto Jovem
16.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(7): 672-675, 2019 Jul 10.
Artigo em Chinês | MEDLINE | ID: mdl-31302908

RESUMO

OBJECTIVE: To explore the genetic basis for three patients with development delay and to correlate their clinical phenotypes with genetic findings. METHODS: The karyotypes of the probands and their parents were analyzed by conventional G-banding. Chromosomal microarray analysis (CMA) was used to detect microdeletion and microduplication. RESULTS: No kartotypic abnormality was detected in the patients and their parents. CMA analysis identified a de novo 3.10 Mb deletion on chromosome 15q24.1q24.2 in case 1, a de novo 3.14 Mb deletion at 15q24.1q24.2 in case 2, and a 3.13 Mb deletion at 15q24.1q24.2 in case 3. All deletions have encompassed the CPLX3,SEMA7A and SIN3A genes. CONCLUSION: The three patients were diagnosed with 15q24 microdeletion syndrome. CPLX3,SEMA7A and SIN3A may be the key genes responsible for this syndrome.


Assuntos
Transtornos Cromossômicos/genética , Deficiência Intelectual/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Antígenos CD/genética , Criança , Deleção Cromossômica , Cromossomos Humanos Par 15/genética , Proteínas Ligadas por GPI/genética , Humanos , Proteínas Repressoras/genética , Semaforinas/genética
17.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(7): 701-703, 2019 Jul 10.
Artigo em Chinês | MEDLINE | ID: mdl-31302915

RESUMO

OBJECTIVE: To explore the genetic basis for a pedigree affected with Bartter's syndrome (BS). METHODS: Panel-based next-generation sequencing (NGS) was carried out to detect mutation in BS-related genes SLC12A1, KCNJ1, BSND and CLCNKB. Sanger sequencing of MAGED2 gene and chromosomal microarray analysis (CMA) were also performed on the patient. Suspected mutation was validated in her family members. RESULTS: No pathogenic mutation was detected by NGS, while a 0.152 Mb microdeletion at Xp11.21 (54 834 585-54 986 301) was found in the male fetus, which removed the entire coding region of the MAGED2 gene. His mother was a heterozygous carrier of the deletion. His father and sister did not carry the same deletion. CONCLUSION: The loss of the MAGED2 gene may underlie the BS in this pedigree.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Antígenos de Neoplasias/genética , Síndrome de Bartter/genética , Deleção de Sequência , Feminino , Testes Genéticos , Heterozigoto , Humanos , Masculino , Mutação , Linhagem
18.
DNA Cell Biol ; 38(9): 955-961, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31361513

RESUMO

The chromatin-remodeling complex ATRX/DAXX is one of the major epigenetic factors that controls heterochromatin maintenance due to its role in histone deposition. ATRX is involved in nucleosome configuration and maintenance of higher order chromatin structure, and DAXX is a specific histone chaperone for H3.3 deposition. Dysfunctions in this complex have been associated with telomere shortening, which influences cell senescence. However, data about this complex in brain tissue related to aging are still scarce. Therefore, in the present study, we analyzed ATRX and DAXX expressions in autopsied human brain specimens and the telomere length. A significant decrease in gene and protein expressions was observed in the brain tissues from the elderly compared with those from the young, which were related to short telomeres. These findings may motivate further functional analysis to confirm the ATRX-DAXX complex involvement in telomere maintenance and brain aging.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Envelhecimento/genética , Encéfalo/metabolismo , Proteínas Nucleares/genética , Proteína Nuclear Ligada ao X/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Encéfalo/crescimento & desenvolvimento , Humanos , Pessoa de Meia-Idade , Proteínas Nucleares/metabolismo , Homeostase do Telômero , Proteína Nuclear Ligada ao X/metabolismo
19.
Jpn J Clin Oncol ; 49(7): 620-627, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31220306

RESUMO

OBJECTIVE: Recurrent hydatidiform moles are reportedly biparental complete moles and related to mutated NLRP7 and KHDC3L. This study was designed to identify mutations of gene NLRP7 and KHDC3L in biparental complete moles. METHODS: In this study, we have screened NLRP7 and KHDC3L mutations in five patients with recurrent moles and five with sporadic moles. Molar tissues and blood samples were collected from patients and their partners. Genotypes of the molar tissues were determined based on short tandem repeat polymorphism. The coding exons of NLRP7 and KHDC3L were sequenced. RESULTS: Two patients with recurrent moles had biparental complete moles, while all other patients had androgenetic complete moles. Three non-synonymous variants in NLRP7 (c.955 G>A, c.1280 T>C and c.1441 G>A) and one in KHDC3L (c.602 C>G) were identified in patients with recurrent moles. NLRP7 c.1441 G>A and c.1280 T>C were mutations found in the Chinese population, while c.1441 G>A was only detected in patients with biparental complete moles in this study. CONCLUSIONS: Genotyping can be used to differentiate biparental complete moles from androgenetic moles and to predict the risk of recurrent moles in future pregnancies. NLRP7 c.1441 G>A may associate with biparental complete moles. Biparental complete moles exhibit genetic heterogeneity.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Grupo com Ancestrais do Continente Asiático/genética , Mola Hidatiforme/genética , Mutação/genética , Recidiva Local de Neoplasia/genética , Proteínas/genética , Neoplasias Uterinas/genética , Adulto , Sequência de Bases , Feminino , Humanos , Mola Hidatiforme/patologia , Masculino , Repetições de Microssatélites/genética , Linhagem , Polimorfismo de Nucleotídeo Único/genética , Gravidez
20.
Int J Mol Sci ; 20(12)2019 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-31216773

RESUMO

The Hippo pathway is important for tissue homeostasis, regulation of organ size andgrowth in most tissues. The co-transcription factor yes-associated protein 1 (YAP1) serves as a maindownstream effector of the Hippo pathway and its dysregulation increases cancer development andblocks colonic tissue repair. Nevertheless, little is known about the transcriptional regulation ofYAP1 in intestinal cells. The aim of this study to identify gene control regions in the YAP1 gene andtranscription factors important for intestinal expression. Bioinformatic analysis of caudal typehomeobox 2 (CDX2) and hepatocyte nuclear factor 4 alpha (HNF4α) chromatin immunoprecipitatedDNA from differentiated Caco-2 cells revealed potential intragenic enhancers in the YAP1 gene.Transfection of luciferase-expressing YAP1 promoter-reporter constructs containing the potentialenhancer regions validated one potent enhancer of the YAP1 promoter activity in Caco-2 and T84cells. Two potential CDX2 and one HNF4α binding sites were identified in the enhancer by in silicotranscription factor binding site analysis and protein-DNA binding was confirmed in vitro usingelectrophoretic mobility shift assay. It was found by chromatin immunoprecipitation experimentsthat CDX2 and HNF4α bind to the YAP1 enhancer in Caco-2 cells. These results reveal a previouslyunknown enhancer of the YAP1 promoter activity in the YAP1 gene, with importance for highexpression levels in intestinal epithelial cells. Additionally, CDX2 and HNF4α binding areimportant for the YAP1 enhancer activity in intestinal epithelial cells.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Fator de Transcrição CDX2/metabolismo , Regulação da Expressão Gênica , Fator 4 Nuclear de Hepatócito/metabolismo , Intestinos , Fosfoproteínas/genética , Regiões Promotoras Genéticas , Sequência de Bases , Sítios de Ligação , Linhagem Celular , Cromatina/genética , Cromatina/metabolismo , Elementos Facilitadores Genéticos , Humanos , Ligação Proteica , Fatores de Transcrição
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