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1.
Medicine (Baltimore) ; 99(19): e20002, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32384455

RESUMO

BACKGROUND: RNA-binding motif protein 3 (RBM3) plays an important role in carcinogenesis and tumor progression. However, the prognostic role of RBM3 in human carcinomas remains controversial. Therefore, we took a meta-analysis to research the association between the overall survival of patients with cancer and the expression of RBM3. METHODS: Systematic literature research identified 17 potentially eligible studies comprising 4976 patients in ten different cancer types. Two researchers independently screened the content and quality of studies and extracted data. Correlations of RBM3 expression and survival were analyzed and the hazard ratios (HRs) with 95% confidence intervals (95% CIs) were calculated. RESULTS: In the pooled analysis, overexpression of RBM3 was related to improved overall survival (OS), recurrence-free survival (RFS), and disease-free survival (DFS) in patients with cancer having a pooled HR of 0.61 (HR = 0.61; 95% CI: 0.47-0.69), 0.57 (HR = 0.60; 95% CI: 0.50-0.71) and 0.54 (HR 0.54; 95% CI: 0.38-0.78). Besides, subgroup analysis proved that overexpression of RBM3 was related to improved OS in colorectal cancer (HR = 0.61, 95% CI: 0.43-0.86), melanoma (HR = 0.32, 95% CI: 0.20-0.52), and gastric cancer (HR = 0.51, 95% CI: 0.35-0.73). However, subgroup analysis according to tumor type revealed that overexpression of RBM3 was not related to better OS in breast carcinoma (HR = 0.52, 95% CI: 0.17-0.61). CONCLUSIONS: Our results indicated that RBM3 overexpression was significantly predictive of better prognosis in various human cancers. For certain tumors, overexpression RBM3 might be a marker of improved survival in humans with cancer, except for breast cancer.


Assuntos
Expressão Gênica , Neoplasias , Proteínas de Ligação a RNA/genética , Humanos , Neoplasias/classificação , Neoplasias/genética , Neoplasias/mortalidade , Prognóstico , Análise de Sobrevida
2.
Science ; 368(6488)2020 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-32299921

RESUMO

Control of messenger RNA (mRNA) decay rate is intimately connected to translation elongation, but the spatial coordination of these events is poorly understood. The Ccr4-Not complex initiates mRNA decay through deadenylation and activation of decapping. We used a combination of cryo-electron microscopy, ribosome profiling, and mRNA stability assays to examine the recruitment of Ccr4-Not to the ribosome via specific interaction of the Not5 subunit with the ribosomal E-site in Saccharomyces cerevisiae This interaction occurred when the ribosome lacked accommodated A-site transfer RNA, indicative of low codon optimality. Loss of the interaction resulted in the inability of the mRNA degradation machinery to sense codon optimality. Our findings elucidate a physical link between the Ccr4-Not complex and the ribosome and provide mechanistic insight into the coupling of decoding efficiency with mRNA stability.


Assuntos
Códon , Elongação Traducional da Cadeia Peptídica , Estabilidade de RNA , Proteínas Repressoras/metabolismo , Ribonucleases/metabolismo , Ribossomos/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Fatores de Transcrição/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Microscopia Crioeletrônica , Complexos Multiproteicos/química , Complexos Multiproteicos/genética , Complexos Multiproteicos/metabolismo , Fatores de Iniciação de Peptídeos/metabolismo , Conformação Proteica em alfa-Hélice , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas Repressoras/química , Proteínas Repressoras/genética , Ribonucleases/química , Ribonucleases/genética , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/genética , Fatores de Transcrição/química , Fatores de Transcrição/genética , Ubiquitina-Proteína Ligases/química , Ubiquitina-Proteína Ligases/genética , Ubiquitinação
3.
Nature ; 580(7803): 386-390, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32296174

RESUMO

The aetiology of inflammatory bowel disease (IBD) is a multifactorial interplay between heredity and environment1,2. Here we report that deficiency in SETDB1, a histone methyltransferase that mediates the trimethylation of histone H3 at lysine 9, participates in the pathogenesis of IBD. We found that levels of SETDB1 are decreased in patients with IBD, and that mice with reduced SETDB1 in intestinal stem cells developed spontaneous terminal ileitis and colitis. SETDB1 safeguards genome stability3, and the loss of SETDB1 in intestinal stem cells released repression of endogenous retroviruses (retrovirus-like elements with long repeats that, in humans, comprise approximately 8% of the genome). Excessive viral mimicry generated by motivated endogenous retroviruses triggered Z-DNA-binding protein 1 (ZBP1)-dependent necroptosis, which irreversibly disrupted homeostasis of the epithelial barrier and promoted bowel inflammation. Genome instability, reactive endogenous retroviruses, upregulation of ZBP1 and necroptosis were all seen in patients with IBD. Pharmaceutical inhibition of RIP3 showed a curative effect in SETDB1-deficient mice, which suggests that targeting necroptosis of intestinal stem cells may represent an approach for the treatment of severe IBD.


Assuntos
Instabilidade Genômica , Histona-Lisina N-Metiltransferase/metabolismo , Doenças Inflamatórias Intestinais/metabolismo , Necroptose , Células-Tronco/metabolismo , Animais , Histona-Lisina N-Metiltransferase/genética , Humanos , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/patologia , Camundongos , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Células-Tronco/citologia
4.
Braz J Med Biol Res ; 53(4): e9290, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32294703

RESUMO

This study was designed to investigate the expression of RBM8A protein in patients with gastric cancer (GC) and to explore its correlation with clinical pathological features as well as prognosis. One hundred pairs of gastric carcinoma tissues and adjacent tissues from patients undergoing gastrectomy for GC were included in this study. The protein expression level of RBM8A was determined by immunohistochemistry using tissue microarrays. We also detected the mRNA expression level of RBM8A in 16 pairs of gastric carcinoma tissues and adjacent tissues. Meanwhile, we predicted the potential correlation between RBM8A and tumor stages as well as survival condition in patents with GC based on The Cancer Genome Atlas (TCGA) database. The correlation of RBM8A with the clinical pathological features and prognosis of the 100 patients with GC was also elucidated. The expression level of RBM8A was significantly higher in gastric carcinoma tissues compared to the adjacent tissues. The protein level of RBM8A was correlated with tumor size (P=0.031), depth of invasion (P<0.001), lymph node metastasis (P<0.001), TNM stage (<0.001), and distant metastasis (P=0.001). Patients with increased RBM8A expression (P<0.0018, 95%CI=0.322-0.871), higher TNM stage (P<0.001, 95%CI=4.990-11.283), and lymph node metastasis (P<0.001, 95%CI=2.873-4.002) had a lower overall survival. Taken together, our study demonstrated that RBM8A may act as a proto-oncogene, which could be a promising biomarker and therapeutic target in the diagnosis and treatment of GC.


Assuntos
Proteínas de Ligação a RNA/metabolismo , Neoplasias Gástricas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Feminino , Mucosa Gástrica/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Proteínas Proto-Oncogênicas/metabolismo , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Análise de Sobrevida
5.
Nature ; 580(7803): 391-395, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32296175

RESUMO

The biological function of Z-DNA and Z-RNA, nucleic acid structures with a left-handed double helix, is poorly understood1-3. Z-DNA-binding protein 1 (ZBP1; also known as DAI or DLM-1) is a nucleic acid sensor that contains two Zα domains that bind Z-DNA4,5 and Z-RNA6-8. ZBP1 mediates host defence against some viruses6,7,9-14 by sensing viral nucleic acids6,7,10. RIPK1 deficiency, or mutation of its RIP homotypic interaction motif (RHIM), triggers ZBP1-dependent necroptosis and inflammation in mice15,16. However, the mechanisms that induce ZBP1 activation in the absence of viral infection remain unknown. Here we show that Zα-dependent sensing of endogenous ligands induces ZBP1-mediated perinatal lethality in mice expressing RIPK1 with mutated RHIM (Ripk1mR/mR), skin inflammation in mice with epidermis-specific RIPK1 deficiency (RIPK1E-KO) and colitis in mice with intestinal epithelial-specific FADD deficiency (FADDIEC-KO). Consistently, functional Zα domains were required for ZBP1-induced necroptosis in fibroblasts that were treated with caspase inhibitors or express RIPK1 with mutated RHIM. Inhibition of nuclear export triggered the Zα-dependent activation of RIPK3 in the nucleus resulting in cell death, which suggests that ZBP1 may recognize nuclear Z-form nucleic acids. We found that ZBP1 constitutively bound cellular double-stranded RNA in a Zα-dependent manner. Complementary reads derived from endogenous retroelements were detected in epidermal RNA, which suggests that double-stranded RNA derived from these retroelements may act as a Zα-domain ligand that triggers the activation of ZBP1. Collectively, our results provide evidence that the sensing of endogenous Z-form nucleic acids by ZBP1 triggers RIPK3-dependent necroptosis and inflammation, which could underlie the development of chronic inflammatory conditions-particularly in individuals with mutations in RIPK1 and CASP817-20.


Assuntos
Inflamação/metabolismo , Necroptose , Proteínas de Ligação a RNA/metabolismo , Transporte Ativo do Núcleo Celular , Animais , Caspase 8/metabolismo , Feminino , Inflamação/genética , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ácidos Nucleicos/metabolismo , RNA de Cadeia Dupla/metabolismo , Proteínas de Ligação a RNA/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Dermatopatias/genética , Dermatopatias/metabolismo , Dermatopatias/patologia
6.
Gene ; 744: 144632, 2020 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-32240777

RESUMO

IGF2BPs, a subclass of RNA-binding proteins, regulate cellular differentiation, proliferation and migration during multiple organs development, but their functions in liver development still remain unclear. Here, in this study, whole-mount in situ hybridization showed that igf2bp1 was constantly and stably expressed at early stages of embryo development in zebrafish. Both the morpholino-induced knockdown and CRISPR/Cas9-mediated knockout of igf2bp1 led to a reduced-size liver phenotype. Further analysis revealed that igf2bp1 is required for hepatic outgrowth, but not for hepatoblast specification and budding. Deficiency of igf2bp1 resulted in reduced cell proliferation, but had no effect on apoptosis. Therefore, we concluded that igf2bp1 is a critical factor to regulate hepatic outgrowth via cell proliferation during early liver development in zebrafish.


Assuntos
Fígado/embriologia , Proteínas de Ligação a RNA/fisiologia , Proteínas de Peixe-Zebra/fisiologia , Animais , Proliferação de Células , Hepatócitos/citologia , Fígado/anatomia & histologia , Fígado/metabolismo , Morfolinos , Tamanho do Órgão , Fenótipo , Proteínas de Ligação a RNA/antagonistas & inibidores , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/antagonistas & inibidores , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
7.
Anticancer Res ; 40(4): 1973-1979, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32234886

RESUMO

BACKGROUND/AIM: The aim of this study was to analyze the expression of nucleolin (NCL) and nucleophosmin (NPM) in prostate adenocarcinoma and in its loco-regional spread in the form of seminal vesicle invasion (SVI). MATERIALS AND METHODS: The study was performed on tissue microarrays of 40 cases of Gleason 3+4 pT3b prostate cancers including tissue samples from SVI. The expression of NCL and NPM was detected immunohistochemically and analyzed with image analysis software. RESULTS: The expression of NCL and NPM were higher in cancer cells within a prostate gland than in SVI. Gleason 4 pattern showed higher expression of NPM than Gleason 3 pattern cells. CONCLUSION: Differences in nuclear NCL and NPM expression in cancer cells between the prostate gland and SVI may indicate involvement of these proteins in loco-regional spread of adenocarcinoma of the prostate. Differences in NPM expression in Gleason 3 and Gleason 4 pattern suggest involvement of this protein in the differentiation of prostate cancer.


Assuntos
Adenocarcinoma/genética , Proteínas Nucleares/genética , Fosfoproteínas/genética , Neoplasias da Próstata/genética , Proteínas de Ligação a RNA/genética , Glândulas Seminais/patologia , Adenocarcinoma/epidemiologia , Adenocarcinoma/patologia , Idoso , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Prognóstico , Próstata/patologia , Antígeno Prostático Específico/genética , Prostatectomia , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/patologia
8.
Medicine (Baltimore) ; 99(15): e19751, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32282736

RESUMO

RATIONALE: This case report expands the mutation and phenotypic spectra of Beaulieu-Boycott-Innes syndrome (BBIS), and will be valuable for mutation-based pre- and post-natal screening of BBIS when conducting a genetic diagnosis. PATIENT CONCERNS: A 4-year old boy from Guilin City, Guangxi Zhuang Autonomous Region, China, was referred to our clinic for clarification of his diagnosis because he showed moderate intellectual disability. DIAGNOSIS: Two novel compound heterozygous mutations of THOC6, c.664T>C (p.Trp222Arg) and c.945+1 G>A were identified in this patient by whole exome sequencing. The two mutations were evaluated as pathogenic and likely pathogenic respectively according to the American College of Medical Genetics guidelines. This is the first case displaying the BBIS phenotype reported in the Chinese population. These two mutations have not been reported previously. INTERVENTIONS: Symptomatic treatment and rehabilitation training for patients. OUTCOMES: The genetic cause of the disease was identified. The family received scientific genetic counseling. LESSONS: BBIS is a rare syndromic autosomal recessive disease with intellectual disability and it is normally difficult for clinicians to recognize it. Whole exome sequencing is an efficient way to identify the gene which causes a particular disease in patients.


Assuntos
Anormalidades Múltiplas/genética , Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Atrofia Muscular/genética , Proteínas de Ligação a RNA/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/reabilitação , Anormalidades Múltiplas/terapia , Grupo com Ancestrais do Continente Asiático/genética , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/reabilitação , Deficiências do Desenvolvimento/terapia , Facies , Aconselhamento Genético/normas , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/reabilitação , Deficiência Intelectual/terapia , Masculino , Atrofia Muscular/diagnóstico , Atrofia Muscular/reabilitação , Atrofia Muscular/terapia , Mutação/genética , Fenótipo , Síndrome , Sequenciamento Completo do Exoma/métodos
9.
Science ; 367(6483): 1230-1234, 2020 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-32165583

RESUMO

How long-lived memories withstand molecular turnover is a fundamental question. Aggregates of a prion-like RNA-binding protein, cytoplasmic polyadenylation element-binding (CPEB) protein, is a putative substrate of long-lasting memories. We isolated aggregated Drosophila CPEB, Orb2, from adult heads and determined its activity and atomic structure, at 2.6-angstrom resolution, using cryo-electron microscopy. Orb2 formed ~75-nanometer-long threefold-symmetric amyloid filaments. Filament formation transformed Orb2 from a translation repressor to an activator and "seed" for further translationally active aggregation. The 31-amino acid protofilament core adopted a cross-ß unit with a single hydrophilic hairpin stabilized through interdigitated glutamine packing. Unlike the hydrophobic core of pathogenic amyloids, the hydrophilic core of Orb2 filaments suggests how some neuronal amyloids could be a stable yet regulatable substrate of memory.


Assuntos
Amiloide/química , Proteínas de Drosophila/química , Memória de Longo Prazo , Neurônios/metabolismo , Agregados Proteicos , Proteínas de Ligação a RNA/química , Fatores de Transcrição/química , Fatores de Poliadenilação e Clivagem de mRNA/química , Animais , Microscopia Crioeletrônica , Drosophila melanogaster , Glutamina/química , Interações Hidrofóbicas e Hidrofílicas , Conformação Proteica
10.
BMC Med Genet ; 21(1): 51, 2020 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-32171285

RESUMO

INTRODUCTION: The AP4B1 gene encodes a subunit of adaptor protein complex-4 (AP4), a component of intracellular transportation of proteins which plays important roles in neurons. Bi-allelic mutations in AP4B1 cause autosomal recessive spastic paraplegia-47(SPG47). CASE PRESENTATION: Here we present a Chinese patient with spastic tetraplegia, moderate psychomotor development delay and febrile seizures plus. Brain MRIs showed dilated supratentorial ventricle, thin posterior and splenium part of corpus callosum. The patient had little progress through medical treatments and rehabilitating regimens. Whole exome sequencing identified novel compound heterozygous truncating variants c.1207C > T (p.Gln403*) and c.52_53delAC (p.Cys18Glnfs*7) in AP4B1 gene. Causal mutations in AP4B1 have been reported in 29 individuals from 22 families so far, most of which are homozygous mutations. CONCLUSIONS: Our study enriched the genetic and phenotypic spectrum of SPG47. Early discovery, diagnosis and proper treatment on the conditions generally increase chances of improvement on the quality of life for patients.


Assuntos
Proteínas de Ligação a DNA/genética , Transtornos Psicomotores/genética , Quadriplegia/genética , Proteínas de Ligação a RNA/genética , Convulsões Febris/genética , Grupo com Ancestrais do Continente Asiático , Criança , China , Códon sem Sentido , Heterozigoto , Humanos , Masculino , Fenótipo , Subunidades Proteicas/genética , Transtornos Psicomotores/complicações , Quadriplegia/complicações , Convulsões Febris/complicações , Sequenciamento Completo do Exoma
11.
Am J Hum Genet ; 106(4): 438-452, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32197073

RESUMO

The neuro-oncological ventral antigen 2 (NOVA2) protein is a major factor regulating neuron-specific alternative splicing (AS), previously associated with an acquired neurologic condition, the paraneoplastic opsoclonus-myoclonus ataxia (POMA). We report here six individuals with de novo frameshift variants in NOVA2 affected with a severe neurodevelopmental disorder characterized by intellectual disability (ID), motor and speech delay, autistic features, hypotonia, feeding difficulties, spasticity or ataxic gait, and abnormal brain MRI. The six variants lead to the same reading frame, adding a common proline rich C-terminal part instead of the last KH RNA binding domain. We detected 41 genes differentially spliced after NOVA2 downregulation in human neural cells. The NOVA2 variant protein shows decreased ability to bind target RNA sequences and to regulate target AS events. It also fails to complement the effect on neurite outgrowth induced by NOVA2 downregulation in vitro and to rescue alterations of retinotectal axonal pathfinding induced by loss of NOVA2 ortholog in zebrafish. Our results suggest a partial loss-of-function mechanism rather than a full heterozygous loss-of-function, although a specific contribution of the novel C-terminal extension cannot be excluded.


Assuntos
Mutação da Fase de Leitura/genética , Proteínas do Tecido Nervoso/genética , Transtornos do Neurodesenvolvimento/genética , Neurônios/fisiologia , Processamento de RNA/genética , Proteínas de Ligação a RNA/genética , Processamento Alternativo/genética , Animais , Orientação de Axônios/genética , Sequência de Bases/genética , Células Cultivadas , Pré-Escolar , Regulação para Baixo/genética , Feminino , Heterozigoto , Humanos , Deficiência Intelectual/genética , Transtornos do Desenvolvimento da Linguagem/genética , Masculino , Camundongos , Hipotonia Muscular/genética , Peixe-Zebra/genética
12.
Am J Hum Genet ; 106(4): 467-483, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32220291

RESUMO

The RNA editing enzyme ADAR2 is essential for the recoding of brain transcripts. Impaired ADAR2 editing leads to early-onset epilepsy and premature death in a mouse model. Here, we report bi-allelic variants in ADARB1, the gene encoding ADAR2, in four unrelated individuals with microcephaly, intellectual disability, and epilepsy. In one individual, a homozygous variant in one of the double-stranded RNA-binding domains (dsRBDs) was identified. In the others, variants were situated in or around the deaminase domain. To evaluate the effects of these variants on ADAR2 enzymatic activity, we performed in vitro assays with recombinant proteins in HEK293T cells and ex vivo assays with fibroblasts derived from one of the individuals. We demonstrate that these ADAR2 variants lead to reduced editing activity on a known ADAR2 substrate. We also demonstrate that one variant leads to changes in splicing of ADARB1 transcript isoforms. These findings reinforce the importance of RNA editing in brain development and introduce ADARB1 as a genetic etiology in individuals with intellectual disability, microcephaly, and epilepsy.


Assuntos
Adenosina Desaminase/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Deficiência Intelectual/genética , Microcefalia/genética , Proteínas de Ligação a RNA/genética , Convulsões/genética , Alelos , Processamento Alternativo/genética , Criança , Pré-Escolar , Células HEK293 , Humanos , Masculino , Processamento de RNA/genética
13.
PLoS Negl Trop Dis ; 14(3): e0008083, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32150556

RESUMO

The rapidly emerging human health crisis associated with the Zika virus (ZIKV) epidemic and its link to severe complications highlights the growing need to identify the mechanisms by which ZIKV accesses hosts. Interferon response protects host cells against viral infection, while the cellular factors that mediate this defense are the products of interferon-stimulated genes (ISGs). Although hundreds of ISGs have been identified, only a few have been characterized for their antiviral potential, target specificity and mechanisms of action. In this work, we focused our investigation on the possible antiviral effect of a novel ISG, C19orf66 in response to ZIKV infection and the associated mechanisms. We found that ZIKV infection could induce C19orf66 expression in ZIKV-permissive cells, and such an overexpression of C19orf66 remarkably suppressed ZIKV replication. Conversely, the depletion of C19orf66 led to a significant increase in viral replication. Furthermore, C19orf66 was found to interact and co-localize with ZIKV nonstructural protein 3 (NS3), thus inducing NS3 degradation via a lysosome-dependent pathway. Taken together, this study identified C19orf66 as a novel ISG that exerts antiviral effects against ZIKV by specifically degrading a viral nonstructural protein. These findings uncovered an intriguing mechanism of C19orf66 that targeting NS3 protein of ZIKV, providing clues for understanding the actions of innate immunity, and affording the possible availability of new drug targets that can be used for therapeutic intervention.


Assuntos
Interações Hospedeiro-Patógeno , Lisossomos/metabolismo , Peptídeo Hidrolases/metabolismo , Proteólise , Proteínas de Ligação a RNA/metabolismo , Proteínas Virais/metabolismo , Zika virus/imunologia , Animais , Humanos , Camundongos , Replicação Viral , Zika virus/crescimento & desenvolvimento
14.
Anticancer Res ; 40(3): 1307-1314, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32132027

RESUMO

BACKGROUND/AIM: Malignant pleural mesothelioma (MPM) is an intractable cancer, and causes of its malignant transformation are not well known. Adenosine deaminase acting on RNA (ADAR) is an RNA-editing enzyme that converts adenosine into inosine in double-stranded RNAs potentially involved in malignant development. MATERIALS AND METHODS: To examine the role of ADAR1 and ADAR2 in MPM, small interfering RNAs (siRNAs) against ADAR1 or ADAR2 were used. RESULTS: Transfection of siRNA against ADAR2 suppressed proliferation, motility, and invasiveness of MPM cells expressing both ADAR1 and ADAR2; however, siRNA against ADAR1 did not affect these cellular activities. Overexpression of ADAR2, that was incapable of binding to RNA, suppressed growth, motility, and invasion of MPM cells. However, overexpression of ADAR2 that had no enzyme activity did not alter the malignant properties of MPM cells. CONCLUSION: Enhancement of the malignant characteristics of cultured MPM cells via ADAR2 was independent of RNA-editing activity.


Assuntos
Adenosina Desaminase/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Mesotelioma/genética , Mesotelioma/metabolismo , Edição de RNA , Proteínas de Ligação a RNA/metabolismo , Adenosina Desaminase/biossíntese , Adenosina Desaminase/genética , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Mesotelioma/enzimologia , Mesotelioma/patologia , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Proteínas de Ligação a RNA/biossíntese , Proteínas de Ligação a RNA/genética , Transfecção
15.
Adv Exp Med Biol ; 1248: 251-263, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32185714

RESUMO

Somatic cells of an organism virtually share the same DNA but it is the timely expression of specific genes that determine their phenotype and cellular identity. A series of complex molecular machinery allows for the regulated process of RNA transcription, splicing, and translation. In addition, microRNAs and specialized RNA binding proteins can trigger the degradation of mRNAs. Long non-coding RNAs can also regulate mRNA fate in multiple ways. In this chapter, we reviewed the RNA processing mechanisms directly regulating immune checkpoint genes. We also cover RNA-based therapeutic strategies aiming at restoring immunity by targeting immune checkpoint genes.


Assuntos
Regulação da Expressão Gênica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Animais , Pontos de Checagem do Ciclo Celular/genética , Pontos de Checagem do Ciclo Celular/imunologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Processamento de RNA , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Mensageiro/uso terapêutico , Proteínas de Ligação a RNA/metabolismo
16.
Nat Struct Mol Biol ; 27(3): 260-273, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32123389

RESUMO

SRSF7 is an essential RNA-binding protein whose misexpression promotes cancer. Here, we describe how SRSF7 maintains its protein homeostasis in murine P19 cells using an intricate negative feedback mechanism. SRSF7 binding to its premessenger RNA promotes inclusion of a poison cassette exon and transcript degradation via nonsense-mediated decay (NMD). However, elevated SRSF7 levels inhibit NMD and promote translation of two protein halves, termed Split-ORFs, from the bicistronic SRSF7-PCE transcript. The first half acts as dominant-negative isoform suppressing poison cassette exon inclusion and instead promoting the retention of flanking introns containing repeated SRSF7 binding sites. Massive SRSF7 binding to these sites and its oligomerization promote the assembly of large nuclear bodies, which sequester SRSF7 transcripts at their transcription site, preventing their export and restoring normal SRSF7 protein levels. We further show that hundreds of human and mouse NMD targets, especially RNA-binding proteins, encode potential Split-ORFs, some of which are expressed under specific cellular conditions.


Assuntos
Regulação da Expressão Gênica , Proteínas de Neoplasias/genética , Fases de Leitura Aberta , Precursores de RNA/genética , Proteínas de Ligação a RNA/genética , Fatores de Processamento de Serina-Arginina/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Sítios de Ligação , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Núcleo Celular/ultraestrutura , Éxons , Homeostase/genética , Camundongos , Células-Tronco Embrionárias Murinas/citologia , Células-Tronco Embrionárias Murinas/metabolismo , Proteínas de Neoplasias/metabolismo , Degradação do RNAm Mediada por Códon sem Sentido , Ligação Proteica , Biossíntese de Proteínas , Precursores de RNA/metabolismo , Proteínas de Ligação a RNA/classificação , Proteínas de Ligação a RNA/metabolismo , Fatores de Processamento de Serina-Arginina/metabolismo , Transcrição Genética
17.
Nat Struct Mol Biol ; 27(3): 297-304, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32157249

RESUMO

Understanding the targeting and spreading patterns of long non-coding RNAs (lncRNAs) on chromatin requires a technique that can detect both high-intensity binding sites and reveal genome-wide changes in spreading patterns with high precision and confidence. Here we determine lncRNA localization using biotinylated locked nucleic acid (LNA)-containing oligonucleotides with toehold architecture capable of hybridizing to target RNA through strand-exchange reaction. During hybridization, a protecting strand competitively displaces contaminating species, leading to highly specific RNA capture of individual RNAs. Analysis of Drosophila roX2 lncRNA using this approach revealed that heat shock, unlike the unfolded protein response, leads to reduced spreading of roX2 on the X chromosome, but surprisingly also to relocalization to sites on autosomes. Our results demonstrate that this improved hybridization capture approach can reveal previously uncharacterized changes in the targeting and spreading of lncRNAs on chromatin.


Assuntos
Cromatina/química , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Oligonucleotídeos/química , RNA Longo não Codificante/química , Proteínas de Ligação a RNA/genética , Cromossomo X/química , Animais , Pareamento de Bases , Sítios de Ligação , Biotinilação , Cromatina/metabolismo , Mapeamento Cromossômico , Cromossomos de Insetos/química , Cromossomos de Insetos/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Resposta ao Choque Térmico , Nanotecnologia/métodos , Hibridização de Ácido Nucleico , Oligonucleotídeos/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Proteínas de Ligação a RNA/metabolismo , Cromossomo X/metabolismo
18.
Arch Virol ; 165(5): 1141-1150, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32222822

RESUMO

Pigs are capable of harbouring influenza A viruses of human and avian origin in their respiratory tracts and thus act as an important intermediary host to generate novel influenza viruses with pandemic potential by genetic reassortment between the two viruses. Here, we show that two distinct H1N2 swine influenza viruses contain avian-like or classical swine-like hemagglutinins with polymerase acidic (PA) and nucleoprotein (NP) genes from 2009 pandemic H1N1 influenza viruses that were found to be circulating in Korean pigs in 2018. Swine H1N2 influenza virus containing an avian-like hemagglutinin gene had enhanced pathogenicity, causing severe interstitial pneumonia in infected pigs and mice. The mortality rate of mice infected with swine H1N2 influenza virus containing an avian-like hemagglutinin gene was higher by 100% when compared to that of mice infected with swine H1N2 influenza virus harbouring classical swine-like hemagglutinin. Further, chemokines attracting inflammatory cells were strongly induced in lung tissues of pigs and mice infected by swine H1N2 influenza virus containing an avian-like hemagglutinin gene. In conclusion, it is necessary for the well-being of humans and pigs to closely monitor swine influenza viruses containing avian-like hemagglutinin with PA and NP genes from 2009 pandemic H1N1 influenza viruses.


Assuntos
Vírus da Influenza A Subtipo H1N2/crescimento & desenvolvimento , Infecções por Orthomyxoviridae/veterinária , Doenças dos Suínos/virologia , Fatores de Virulência/genética , Animais , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Vírus da Influenza A Subtipo H1N2/genética , Vírus da Influenza A Subtipo H1N2/isolamento & purificação , Vírus da Influenza A Subtipo H1N2/patogenicidade , Camundongos , Infecções por Orthomyxoviridae/patologia , Infecções por Orthomyxoviridae/virologia , Proteínas de Ligação a RNA/genética , Análise de Sobrevida , Suínos , Doenças dos Suínos/patologia , Proteínas do Core Viral/genética , Virulência
19.
Medicine (Baltimore) ; 99(3): e18791, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32011477

RESUMO

p62 is a multifunctional protein involved in multiple cellular processes including proliferation, drug sensitivity and autophagy-associated cancer cell growth. However, the role of p62 in colon cancer remains controversial. Here we investigated the expression of p62 protein in colon cancer and its clinical significance.Patients with colon adenocarcinoma who underwent resection at the Third Affiliated Teaching Hospital of Xinjiang Medical University (Affiliated Cancer Hospital) were retrospectively analyzed. The expression of p62 protein in tumor tissues and adjacent normal tissues was detected by immunohistochemistry and western-blotting. Real-time quantitative polymerase chain reaction was used to detect the expression level of p62 messenger ribonucleic acid in specimens. Progression-free survival (PFS) and overall survival (OS) were assessed using Kaplan-Meier method and the log-rank test.A total of 85 colon cancer patients were enrolled, including 55 (64.71%) patients with high p62 expression, and 30 (35.29%) patients with low p62 expression. The transcription and expression level of p62 in colon cancer tissues were higher than those in adjacent normal tissues (P < .01). High expression of p62 was an independent risk factor for the poor prognosis (PFS and OS) of colon cancer.p62 may be a potential indicator of determining the progression and prognosis evaluation of colon cancer.


Assuntos
Adenocarcinoma/metabolismo , Neoplasias do Colo/metabolismo , Proteínas de Ligação a RNA/metabolismo , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Biomarcadores Tumorais/metabolismo , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Neoplasias do Colo/cirurgia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , RNA Mensageiro/metabolismo , Estudos Retrospectivos , Análise de Sobrevida
20.
Gene ; 738: 144473, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32057929

RESUMO

Cytoplasmic polyadenylation element binding proteins (CPEBs) are widely conserved proteins that regulate the length of poly(A) tails in the cytoplasm, regulate translation, and regulate mRNA transport. While CPEBs are best known for regulating maternal messages in oocytes, CPEBs also have roles in many other cell types including neurons. Here we extend our knowledge of the roles of CPEBs in neurons by showing that the Drosophila CPEB-encoding gene, orb, is required for proper dendrite development in larval sensory dendritic arborization neurons. Furthermore, we provide evidence that orb is important for neuron cell fate specification.


Assuntos
Dendritos/metabolismo , Proteínas de Drosophila/metabolismo , Neurônios/metabolismo , Proteínas de Ligação a RNA/metabolismo , Animais , Linhagem da Célula/fisiologia , Citoplasma/metabolismo , Proteínas de Drosophila/fisiologia , Drosophila melanogaster/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Larva/genética , Neurogênese/fisiologia , Proteínas de Ligação a Poli(A)/metabolismo , Poliadenilação , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/fisiologia , Fatores de Transcrição/genética
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