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2.
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
3.
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
4.
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
5.
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
6.
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
7.
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
8.
Nat Commun ; 10(1): 2510, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-31175290

RESUMO

Metastasis-associated recurrence is the major cause of poor prognosis in hepatocellular carcinoma (HCC), however, the underlying mechanisms remain largely elusive. In this study, we report that expression of choroideremia-like (CHML) is increased in HCC, associated with poor survival, early recurrence and more satellite nodules in HCC patients. CHML promotes migration, invasion and metastasis of HCC cells, in a Rab14-dependent manner. Mechanism study reveals that CHML facilitates constant recycling of Rab14 by escorting Rab14 to the membrane. Furthermore, we identify several metastasis regulators as cargoes carried by Rab14-positive vesicles, including Mucin13 and CD44, which may contribute to metastasis-promoting effects of CHML. Altogether, our data establish CHML as a potential promoter of HCC metastasis, and the CHML-Rab14 axis may be a promising therapeutic target for HCC.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Neoplasias Primárias Múltiplas/metabolismo , Proteínas rab de Ligação ao GTP/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/secundário , Células HEK293 , Humanos , Receptores de Hialuronatos/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Nus , Mucinas/metabolismo , Invasividade Neoplásica , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Transplante de Neoplasias , Neoplasias Primárias Múltiplas/patologia , RNA Mensageiro/metabolismo , Carga Tumoral
9.
Biol Res ; 52(1): 31, 2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-31182157

RESUMO

BACKGROUND: The purpose of the present study was to investigate the role of the methylation status of the DACT1 gene on the invasion and metastasis of nasopharyngeal carcinoma cells. METHODS: The levels of methylation and expression of the DACT1 gene in nasopharyngeal carcinoma tissues and CNE2 cells were determined by methylation-specific PCR and RT-PCR, respectively. CNE2 cells were treated with 5-aza-2-deoxycytidine, and the variation in the methylation status of the DACT1 gene was detected, as well as the influence of methylation on invasiveness of nasopharyngeal carcinoma cells. RESULTS: The DACT1 gene was hyper-methylated in 44 of 62 cases of nasopharyngeal carcinoma. The DACT1 gene was hyper-methylated in 32 of 38 cases of nasopharyngeal carcinoma with lymph node metastasis, and the DACT1 gene was hyper-methylated in 7 of 24 cases of nasopharyngeal carcinoma without lymph node metastasis. The DACT1 mRNA level was weakly expressed or not expressed in all nasopharyngeal carcinoma tissues with hyper-methylated DACT1 genes; however, the DACT1 mRNA level was highly expressed in nasopharyngeal carcinoma tissues with low expression of the methylated DACT1 gene. The DACT1 gene was hyper-methylated and not expressed in CNE2 cells that did not have 5-aza-2-deoxycytidine treatment. After 5-aza-2-deoxycytidine treatment, the DACT1 gene was demethylated and the expression of DACT1 was restored. Moreover, the invasion ability was inhibited in CNE2 cells treated with 5-aza-2-deoxycytidine. CONCLUSION: The expression of DACT1 was related to the methylation status. High expression of DACT1 may inhibit the invasion and metastasis of nasopharyngeal carcinoma cells.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Metilação de DNA/genética , Carcinoma Nasofaríngeo/secundário , Neoplasias Nasofaríngeas/patologia , Proteínas Nucleares/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Metilação de DNA/fisiologia , Feminino , Humanos , Masculino , Carcinoma Nasofaríngeo/genética , Neoplasias Nasofaríngeas/genética , Invasividade Neoplásica , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Regiões Promotoras Genéticas
10.
Genes Dev ; 33(13-14): 828-843, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31171701

RESUMO

Adenovirus transformed cells have a dedifferentiated phenotype. Eliminating E1A in transformed human embryonic kidney cells derepressed ∼2600 genes, generating a gene expression profile closely resembling mesenchymal stem cells (MSCs). This was associated with a dramatic change in cell morphology from one with scant cytoplasm and a globular nucleus to one with increased cytoplasm, extensive actin stress fibers, and actomyosin-dependent flattening against the substratum. E1A-induced hypoacetylation at histone H3 Lys27 and Lys18 (H3K27/18) was reversed. Most of the increase in H3K27/18ac was in enhancers near TEAD transcription factors bound by Hippo signaling-regulated coactivators YAP and TAZ. E1A causes YAP/TAZ cytoplasmic sequestration. After eliminating E1A, YAP/TAZ were transported into nuclei, where they associated with poised enhancers with DNA-bound TEAD4 and H3K4me1. This activation of YAP/TAZ required RHO family GTPase signaling and caused histone acetylation by p300/CBP, chromatin remodeling, and cohesin loading to establish MSC-associated enhancers and then superenhancers. Consistent results were also observed in primary rat embryo kidney cells, human fibroblasts, and human respiratory tract epithelial cells. These results together with earlier studies suggest that YAP/TAZ function in a developmental checkpoint controlled by signaling from the actin cytoskeleton that prevents differentiation of a progenitor cell until it is in the correct cellular and tissue environment.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas E1A de Adenovirus/metabolismo , Diferenciação Celular/genética , Inativação Gênica , Peptídeos e Proteínas de Sinalização Intracelular/genética , Fosfoproteínas/genética , Citoesqueleto de Actina/metabolismo , Adenoviridae , Animais , Células Cultivadas , Células HEK293 , Humanos , Ratos , Transdução de Sinais
11.
Gene ; 706: 69-76, 2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31054365

RESUMO

The receptor for activated c-kinase (RACK1, Asc1 in yeast) is a eukaryotic ribosomal protein located in the head region of the 40S subunit near the mRNA exit channel. This WD-repeat ß-propeller protein acts as a signaling molecule and is involved in metabolic regulation, cell cycle progression, and translational control. However, the exact details of the RACK1 recruitment and stable association with the 40S ribosomal subunit remain only partially known. X-ray analyses of the yeast, Saccharomyces cerevisiae, ribosome revealed that the RACK1 propeller blade (4-5) interacts with the eukaryote-specific C-terminal domain (CTD) of ribosomal protein S3 (uS3 family). To check the functional significance of this interaction, we generated mutant yeast strains harboring C-terminal deletions of uS3. We found that deletion of the 20 C-terminal residues (interacting with blade 4-5) from the uS3-CTD abrogates RACK1 binding to the ribosome. Strains with truncated uS3-CTD exhibited compromised cellular growth and protein synthesis similar to that of RACK1Δ strain, thus suggesting that the uS3-CTD is crucial not only for the recruitment and association of RACK1 with the ribosome, but also for its intracellular function. We suggest that eukaryote-specific RACK1-uS3 interaction has evolved to act as a link between the ribosome and the cellular signaling pathways.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Receptores de Quinase C Ativada/metabolismo , Proteínas Ribossômicas/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas de Ligação ao GTP/genética , Ligação Proteica , Biossíntese de Proteínas , RNA Mensageiro/genética , Receptores de Quinase C Ativada/genética , Proteínas Ribossômicas/genética , Subunidades Ribossômicas Menores de Eucariotos/química , Ribossomos/química , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Fatores de Transcrição/genética
12.
Nat Commun ; 10(1): 2201, 2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-31101814

RESUMO

Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease. It is thought that many common variant gene loci of weak effect act additively to predispose to common autoimmune diseases, while the contribution of rare variants remains unclear. Here we describe that rare coding variants in lupus-risk genes are present in most SLE patients and healthy controls. We demonstrate the functional consequences of rare and low frequency missense variants in the interacting proteins BLK and BANK1, which are present alone, or in combination, in a substantial proportion of lupus patients. The rare variants found in patients, but not those found exclusively in controls, impair suppression of IRF5 and type-I IFN in human B cell lines and increase pathogenic lymphocytes in lupus-prone mice. Thus, rare gene variants are common in SLE and likely contribute to genetic risk.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/genética , Proteínas de Membrana/genética , Quinases da Família src/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adolescente , Adulto , Animais , Linfócitos B/citologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Estudos de Casos e Controles , Linhagem Celular , Núcleo Celular/imunologia , Núcleo Celular/metabolismo , Criança , Modelos Animais de Doenças , Feminino , Frequência do Gene , Células HEK293 , Voluntários Saudáveis , Humanos , Fatores Reguladores de Interferon/imunologia , Fatores Reguladores de Interferon/metabolismo , Interferon Tipo I/imunologia , Interferon Tipo I/metabolismo , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação de Sentido Incorreto , Sequenciamento Completo do Exoma , Quinases da Família src/metabolismo
13.
N Engl J Med ; 380(20): 1918-1928, 2019 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-31091373

RESUMO

BACKGROUND: In the context of kidney transplantation, genomic incompatibilities between donor and recipient may lead to allosensitization against new antigens. We hypothesized that recessive inheritance of gene-disrupting variants may represent a risk factor for allograft rejection. METHODS: We performed a two-stage genetic association study of kidney allograft rejection. In the first stage, we performed a recessive association screen of 50 common gene-intersecting deletion polymorphisms in a cohort of kidney transplant recipients. In the second stage, we replicated our findings in three independent cohorts of donor-recipient pairs. We defined genomic collision as a specific donor-recipient genotype combination in which a recipient who was homozygous for a gene-intersecting deletion received a transplant from a nonhomozygous donor. Identification of alloantibodies was performed with the use of protein arrays, enzyme-linked immunosorbent assays, and Western blot analyses. RESULTS: In the discovery cohort, which included 705 recipients, we found a significant association with allograft rejection at the LIMS1 locus represented by rs893403 (hazard ratio with the risk genotype vs. nonrisk genotypes, 1.84; 95% confidence interval [CI], 1.35 to 2.50; P = 9.8×10-5). This effect was replicated under the genomic-collision model in three independent cohorts involving a total of 2004 donor-recipient pairs (hazard ratio, 1.55; 95% CI, 1.25 to 1.93; P = 6.5×10-5). In the combined analysis (discovery cohort plus replication cohorts), the risk genotype was associated with a higher risk of rejection than the nonrisk genotype (hazard ratio, 1.63; 95% CI, 1.37 to 1.95; P = 4.7×10-8). We identified a specific antibody response against LIMS1, a kidney-expressed protein encoded within the collision locus. The response involved predominantly IgG2 and IgG3 antibody subclasses. CONCLUSIONS: We found that the LIMS1 locus appeared to encode a minor histocompatibility antigen. Genomic collision at this locus was associated with rejection of the kidney allograft and with production of anti-LIMS1 IgG2 and IgG3. (Funded by the Columbia University Transplant Center and others.).


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Variações do Número de Cópias de DNA , Rejeição de Enxerto/genética , Transplante de Rim , Proteínas com Domínio LIM/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Estudos de Coortes , Estudos de Associação Genética , Genótipo , Antígenos HLA/genética , Teste de Histocompatibilidade , Humanos , Imunoglobulina G/sangue , Proteínas com Domínio LIM/imunologia , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Polimorfismo de Nucleotídeo Único , Doadores de Tecidos
14.
Nan Fang Yi Ke Da Xue Xue Bao ; 39(3): 286-291, 2019 Mar 30.
Artigo em Chinês | MEDLINE | ID: mdl-31068306

RESUMO

OBJECTIVE: To investigate the effects of Yes-associated protein 1 (YAP1) knockdown on the proliferation, migration and invasion in human nasopharyngeal carcinoma (NPC) cells. METHODS: We detected the expression of YAP1 mRNA and protein in different NPC cell lines and an immortalized nasopharyngeal epithelial cell line using RT-PCR and Western blotting. Two YAP1-targeting small interfering RNAs (siRNA) were transfected into NPC cell lines S26 and S18, and the knockdown efficiency was confirmed by RT-PCR and Western blotting. The effect of YAP1 knockdown on the proliferation of the NPC cells was determined by cell counting and colony formation assay; wound healing assay and Transwell assay were used to analyze the changes in the cell migration and invasion abilities in each group. Western blotting was used to analyze the changes in the expressions of c-myc, E-cadherin, N-cadherin and vimentin in the NPC cells after YAP1 knockdown. RESULTS: YAP1 was highly expressed in the NPC cell lines. Compared with the negative control group, the NPC cell lines with YAP1 knockdown showed significantly lowered YAP1 expressions at both the mRNA and protein levels (P < 0.05). YAP1 knockdown significantly suppressed the growth, cloning formation, migration and invasion of the NPC cells as compared with control cells (P < 0.01). YAP1 knockdown obviously decreased the expression levels of c-myc, N-cadherin and vimentin and increased E-cadherin expression in the NPC cells. CONCLUSIONS: YAP1 knockdown via siRNA suppresses the proliferation, migration and invasion of NPC cells in vitro, suggesting that YAP1 may serve as a therapeutic target for NPC.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Carcinoma Nasofaríngeo , Fosfoproteínas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Carcinoma Nasofaríngeo/genética , Invasividade Neoplásica , Fosfoproteínas/genética
15.
Iran J Allergy Asthma Immunol ; 18(2): 218-224, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31066258

RESUMO

The mustard lung is a late consequence of exposure to sulfur mustard (SM) in veterans who had participated in the Iraq-Iran war. Three mechanisms are contributed in the pathogenesis of mustard lung including oxidative stress, protease-antiprotease imbalance, and dysregulated immune response. In the context of the immune response, the role of the inflammasome complex and their inflammatory cytokines are important. This study aims to investigate the inflammasome pathway and their inflammatory cytokine (i.e IL-1 and IL-18) in the peripheral blood of mustard lung patients as well as chronic obstructive pulmonary disease (COPD) patients. This research was conducted as a cross-sectional analytical study on 15 SM patients and was compared with 15 COPD patients and 15 healthy controls. The real-time polymerase chain reaction was used to assess gene expression levels of inflammasome components (NLRP1, NLRP3, NLRC4, and ASC), inflammatory cytokines (IL-1ß, IL-18, and IL-1ßR), and IL-37 as an anti-inflammatory cytokine. Finally, the data were analyzed by SPSS version 21 software. The gene expression level of molecules involved in inflammasome pathway showed a slight increase in the peripheral blood of SM and COPD patients compared to the control group. However, this difference was not statistically significant. Only IL-37 and NLRP1 had a significant increase in mustard lung and COPD patients; compared to healthy controls (p<0.05). Due to the normal expression of genes involved in the inflammasome pathway, it can be stated that the inflammasome pathway is not active in the blood of mustard lung patients.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Substâncias para a Guerra Química/efeitos adversos , Inflamassomos/metabolismo , Interleucina-1/metabolismo , Pneumopatias/imunologia , Gás de Mostarda/efeitos adversos , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Reguladoras de Apoptose/genética , Estudos Transversais , Exposição Ambiental/efeitos adversos , Feminino , Humanos , Mediadores da Inflamação/sangue , Interleucina-1/sangue , Interleucina-1/genética , Interleucina-18/sangue , Guerra do Iraque 2003-2011 , Pneumopatias/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/imunologia , Veteranos
16.
Dis Markers ; 2019: 7945429, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31089398

RESUMO

Background: ASAP1 (also known as AMAP1 or DDEF1) encodes an Arf GTPase-activating protein (Arf GAP), a multifunctional scaffold protein that induces hydrolysis of GTP bound to the ADP-ribosylation factor (Arf) family GTP-binding proteins. Reduction of ASAP1 expression in vitro was related to suppression of cell migration and invasiveness. The genetic variant rs4733781 of the ASAP1 gene was revealed as a significant locus for tuberculosis (TB) susceptibility, but the results still need to be validated. Methods: Blood samples from a total of 1914 active TB and healthy controls (HC) were collected to evaluate rs4733781 and the risk of TB. Meanwhile, a total of 48 noninfected HC, latent TB-infected (LTBI) controls, and active TB were collected to assay ASAP1 expression difference among the three groups. The QuantiFERON-TB Gold In-Tube was adopted to identify noninfected HC and LTBI. Results: The genetic variant of rs4733781 was found to be significantly associated with TB, and the A allele of rs4733781 (C>A) was 0.38 and 0.43 among TB cases and HC, respectively (P = 0.0035). Meanwhile, the peripheral blood monocyte RNA fold changes for the ASAP1 gene among the 16 HC, 16 LTBI, and 16 active TB were 1.088 ± 0.4919, 2.237 ± 0.6505, and 10.12 ± 10.98 (F = 9.559, P = 0.0003), respectively, and the expression of ASAP1 was increased by 2.06-fold (P < 0.0001) and 9.30-fold (P < 0.0052) for LTBI and active TB, when compared to the HC. Conclusions: Our data indicated that the A allele of rs4733781 for the ASAP1 gene was in association with a decreased risk of TB. But not only that, the overexpression of the ASAP1 gene among LTBI and TB was related to the progression of TB, which further implies that the expression of ASAP1 would be a potential biomarker for LTBI and TB diagnoses.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Polimorfismo de Nucleotídeo Único , Tuberculose/genética , Proteínas Adaptadoras de Transdução de Sinal/sangue , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Biomarcadores/sangue , Células Cultivadas , China , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Tuberculose/sangue
17.
Fish Shellfish Immunol ; 90: 126-133, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31059814

RESUMO

To investigate the role of the Rab7 effector RILP (Rab-interacting lysosomal protein) in white spot syndrome virus (WSSV) infection, the full-length cDNA of RILP (LvRILP) was cloned in Litopenaeus vannamei, which consists of 1595 bp and encodes a polypeptide of 411 amino acids. Sequence analysis and multiple sequence alignment displayed that LvRILP contained a conserved RILP region from 277 amino acid to 325 amino acid. Both the LvRILP and Rab7 mRNA were most highly expressed in stomach and most lowly expressed in hemocyte, which were significantly up-regulated and exhibited similar kinetics post WSSV infection. The interaction of Rab7 with LvRILP was verified by both GST Pull-down and ELISA. Meanwhile, the results of Pull-down assays showed that the GST-tagged VP28 (GST-VP28), His-tagged Rab7 (His-Rab7) and His-RILP formed a tripartite complex. After silencing by specific LvRILP dsRNA, the LvRILP mRNA level exhibited a significant reduction, and the expression levels of three WSSV genes ie1, wsv477 and vp28 all exhibited decreases at 24, 36 and 48 h post WSSV infection. These results suggested that the Rab7 effector RILP was involved in WSSV infection.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Penaeidae/genética , Penaeidae/imunologia , Proteínas Adaptadoras de Transdução de Sinal/química , Sequência de Aminoácidos , Animais , Proteínas de Artrópodes/química , Proteínas de Artrópodes/genética , Proteínas de Artrópodes/imunologia , Perfilação da Expressão Gênica , Filogenia , Alinhamento de Sequência , Vírus da Síndrome da Mancha Branca 1/fisiologia
18.
Sci Total Environ ; 678: 611-617, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31078851

RESUMO

Extensive epidemiological studies have revealed that nearly 25% of the premature mortality from lung cancer is attributed to regional haze caused by a high level of fine particulate matter (PM2.5). The nitro-PAHs (NPAHs), with a lower volatility, are more likely to be absorbed with PM2.5 and to pose a threat to health, whereas there is insufficient information about carcinogenesis caused by NPAHs. Our study evaluated the carcinogenic effect of typical NPAHs on lung cancer cell adhesion and metastasis and revealed the possibly involved mechanism through in vitro experiments. For the specific mechanism, typical NPAHs could directly induce the inactivation of serine/threonine kinase (MST1/2) and large tumor suppressor (LATS1/2) and result in the nuclear translocation of Yes-associated protein (YAP). The nuclear YAP would then combine with TEA domain transcription factor (TEAD) and profoundly influence the transcription of migration and adhesion genes related to lung cancer metastasis. These findings remind us of the possible carcinogenicity of NPAHs absorbed with PM2.5 and provide a reference for the prevention and mitigation of tumorigenesis in a heavily polluted environment.


Assuntos
Transformação Celular Neoplásica , Transição Epitelial-Mesenquimal , Nitrocompostos/efeitos adversos , Material Particulado/efeitos adversos , Hidrocarbonetos Policíclicos Aromáticos/efeitos adversos , Transdução de Sinais/efeitos dos fármacos , Células A549 , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Poluentes Atmosféricos/efeitos adversos , Adesão Celular , Humanos , Neoplasias Pulmonares/patologia , Metástase Neoplásica/fisiopatologia , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo
19.
BMC Genomics ; 20(1): 395, 2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31113383

RESUMO

BACKGROUND: Many genome-wide association studies have detected genomic regions associated with traits, yet understanding the functional causes of association often remains elusive. Utilizing systems approaches and focusing on intermediate molecular phenotypes might facilitate biologic understanding. RESULTS: The availability of exome sequencing of two populations of African-Americans and European-Americans from the Atherosclerosis Risk in Communities study allowed us to investigate the effects of annotated loss-of-function (LoF) mutations on 122 serum metabolites. To assess the findings, we built metabolomic causal networks for each population separately and utilized structural equation modeling. We then validated our findings with a set of independent samples. By use of methods based on concepts of Mendelian randomization of genetic variants, we showed that some of the affected metabolites are risk predictors in the causal pathway of disease. For example, LoF mutations in the gene KIAA1755 were identified to elevate the levels of eicosapentaenoate (p-value = 5E-14), an essential fatty acid clinically identified to increase essential hypertension. We showed that this gene is in the pathway to triglycerides, where both triglycerides and essential hypertension are risk factors of metabolomic disorder and heart attack. We also identified that the gene CLDN17, harboring loss-of-function mutations, had pleiotropic actions on metabolites from amino acid and lipid pathways. CONCLUSION: Using systems biology approaches for the analysis of metabolomics and genetic data, we integrated several biological processes, which lead to findings that may functionally connect genetic variants with complex diseases.


Assuntos
Pleiotropia Genética , Genoma Humano , Metaboloma/genética , Metabolômica , Mutação , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Afro-Americanos/genética , Algoritmos , Grupo com Ancestrais do Continente Europeu/genética , Humanos
20.
MBio ; 10(3)2019 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-31064828

RESUMO

Viral infections induce proinflammatory signaling cascades and inflammatory cytokine production, which is precisely regulated for host benefits. In the current study, we unravel a previously unappreciated role of nonmuscle myosin heavy chain IIA (NMHC-IIA) as a negative regulator in inflammatory responses. We identified that cell surface NMHC-IIA recognized sialic acids on sialylated RNA viruses during early infections and interacted with an immune adaptor DNAX activation protein of 12 kDa (DAP12) to recruit downstream spleen tyrosine kinase (Syk), leading to suppressed virus-triggered proinflammatory responses. More importantly, recognition of sialylated RNA viruses or sialic acid mimics by NMHC-IIA was shown to inhibit lipopolysaccharide (LPS)-induced proinflammatory responses via the DAP12-Syk pathway. These findings uncover a novel negative regulation mechanism of proinflammatory responses and provide a molecular basis to design anti-inflammatory drugs.IMPORTANCE NMHC-IIA, a subunit of nonmuscle myosin IIA (NM-IIA), takes part in diverse physiological processes, including cell movement, cell shape maintenance, and signal transduction. Recently, NMHC-IIA has been demonstrated to be a receptor or factor contributing to viral infections. Here, we identified that NMHC-IIA recognizes sialic acids on sialylated RNA viruses, vesicular stomatitis virus (VSV) and porcine reproductive and respiratory syndrome virus (PRRSV). Upon recognition, NMHC-IIA associates with the transmembrane region of DAP12 to recruit Syk. Activation of the DAP12-Syk pathway impairs the host antiviral proinflammatory cytokine production and signaling cascades. More importantly, sialic acid mimics and sialylated RNA viruses enable the antagonism of LPS-triggered proinflammatory responses through engaging the NMHC-IIA-DAP12-Syk pathway. These results actually support that NMHC-IIA is involved in negative modulation of the host innate immune system, which provides a molecular basis for prevention and control of the sialylated RNA viruses and treatment of inflammatory diseases.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Cadeias Pesadas de Miosina/metabolismo , Vírus de RNA/metabolismo , Ácidos Siálicos/metabolismo , Transdução de Sinais , Quinase Syk/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Proteínas do Citoesqueleto/metabolismo , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Imunidade Inata , Camundongos , Cadeias Pesadas de Miosina/genética , Células RAW 264.7 , Suínos , Quinase Syk/genética
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