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2.
Microbiome ; 2: 14, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25071935

RESUMO

BACKGROUND: Cystic fibrosis (CF) is caused by mutations in the CFTR gene that predispose the airway to infection. Chronic infection by pathogens such as Pseudomonas aeruginosa leads to inflammation that gradually degrades lung function, resulting in morbidity and early mortality. In a previous study of CF monozygotic twins, we demonstrate that genetic modifiers significantly affect the establishment of persistent P. aeruginosa colonization in CF. Recognizing that bacteria other than P. aeruginosa contribute to the CF microbiome and associated pathology, we used deep sequencing of sputum from pediatric monozygotic twins and nontwin siblings with CF to characterize pediatric bacterial communities and the role that genetics plays in their evolution. FINDINGS: We found that the microbial communities in sputum from pediatric patients living together were much more alike than those from pediatric individuals living apart, regardless of whether samples were taken from monozygous twins or from nontwin CF siblings living together, which we used as a proxy for dizygous twins. In contrast, adult communities were comparatively monolithic and much less diverse than the microbiome of pediatric patients. CONCLUSION: Taken together, these data and other recent studies suggest that as patients age, the CF microbiome becomes less diverse, more refractory to treatment and dominated by mucoid P. aeruginosa, as well as being associated with accelerated pulmonary decline. Our studies show that the microbiome of pediatric patients is susceptible to environmental influences, suggesting that interventions to preserve the community structure found in young CF patients might be possible, perhaps slowing disease progression.

3.
J Pediatr ; 165(4): 830-5.e2, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25027361

RESUMO

OBJECTIVE: To understand the triggers that may impact respiratory health in cystic fibrosis (CF), including the effects of pets, because environmental factors contribute to one-half of the variation in lung function in patients with CF. STUDY DESIGN: A total of 703 subjects with CF were recruited through the US CF Twin-Sibling Study. Questionnaires were used to determine the presence/absence of cats and dogs in households with a child with CF. Questionnaires, chart review, and US CF Foundation Patient Registry data were used to track respiratory and infection outcomes. RESULTS: Within the sample, 47% of subjects reported owning a dog, and 28% reported owning a cat. After adjustment for demographic factors, dog ownership was not associated with any adverse clinical outcomes, and cat ownership was associated an increased risk in developing nasal polyps (aOR 1.66; P = .024) compared with noncat owners. Subjects who owned both cats and dogs were twice as likely to report wheezing compared with other subjects (aOR: 2.01; P = .009). There were no differences in prevalence and age of acquisition for the common CF respiratory pathogens Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus between cat/dog owners and noncat/dog owners. CONCLUSIONS: Cat ownership was associated with a greater frequency of developing nasal polyps and combined cat-dog ownership was associated with a greater rate of wheezing. Prospective studies are needed to confirm these associations and the potential psychosocial benefits of cat and/or dog ownership.


Assuntos
Gatos , Fibrose Cística/fisiopatologia , Cães , Animais de Estimação , Transtornos Respiratórios/complicações , Adolescente , Adulto , Fatores Etários , Animais , Criança , Pré-Escolar , Fibrose Cística/complicações , Feminino , Humanos , Lactente , Masculino , Staphylococcus aureus Resistente à Meticilina , Pessoa de Meia-Idade , Morbidade , Prevalência , Pseudomonas aeruginosa , Sistema de Registros , Respiração , Sons Respiratórios , Fatores de Risco , Irmãos , Inquéritos e Questionários , Resultado do Tratamento , Adulto Jovem
5.
Pediatr Pulmonol ; 48(9): 857-64, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23143815

RESUMO

BACKGROUND: Cystic fibrosis (CF) is characterized by recurrent respiratory infections and progressive lung disease. Although environmental factors account for 50% of the variation in CF lung function, few specific exposures have been identified. Studies using small study samples focusing on environmental allergies in CF have had inconsistent results. Our objective was to examine the role of environmental allergies in upper and lower respiratory tract morbidities in CF. METHODS: A total of 1,321 subjects with CF were recruited through the U.S. CF Twin-Sibling Study. Questionnaires were used to determine the presence/absence of environmental allergies. Questionnaires, chart review, and U.S. CF Foundation Patient Registry data were used to track outcomes. RESULTS: Within the study sample 14% reported environmental allergies. Environmental allergies were associated with a higher risk of sinus disease (adjusted OR: 2.68; P < 0.001) and nasal polyps (adjusted OR: 1.74; P = 0.003). Environmental allergies were also associated with a more rapid decline in lung function (additional -1.1%/year; P = 0.001). However, allergies were associated with a later median age of acquisition of Pseudomonas aeruginosa (6.6 years vs. 4.4 years; log rank P = 0.027). The reported use of common allergy medications, anti-histamines and leukotriene inhibitors, did not alter the frequency of respiratory morbidities. CONCLUSIONS: Environmental allergies are associated with an increased risk of sinus disease and nasal polyps and a more rapid decline in CF lung function, but may have a protective effect against the acquisition of P. aeruginosa. Prospective studies are needed to confirm these associations which have implications for more aggressive management of allergies.


Assuntos
Fibrose Cística/complicações , Fibrose Cística/fisiopatologia , Hipersensibilidade/complicações , Hipersensibilidade/fisiopatologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Volume Expiratório Forçado/fisiologia , Humanos , Lactente , Recém-Nascido , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Razão de Chances , Infecções por Pseudomonas/complicações , Infecções por Pseudomonas/fisiopatologia , Testes de Função Respiratória/métodos , Testes de Função Respiratória/estatística & dados numéricos , Inquéritos e Questionários , Adulto Jovem
6.
J Pediatr ; 161(2): 290-5.e1, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22364820

RESUMO

OBJECTIVE: To quantify the relative contribution of factors other than cystic fibrosis transmembrane conductance regulator genotype and environment on the acquisition of Pseudomonas aeruginosa (Pa) by patients with cystic fibrosis. STUDY DESIGN: Lung infection with Pa and mucoid Pa was assessed using a co-twin study design of 44 monozygous (MZ) and 17 dizygous (DZ) twin pairs. Two definitions were used to establish infection: first positive culture and persistent positive culture. Genetic contribution to infection (ie, heritability) was estimated based on concordance analysis, logistic regression, and age at onset of infection through comparison of intraclass correlation coefficients. RESULTS: Concordance for persistent Pa infection was higher in MZ (0.83; 25 of 30 pairs) than DZ twins (0.45; 5 of 11 pairs), generating a heritability of 0.76. Logistic regression adjusted for age corroborated genetic control of persistent Pa infection. The correlation for age at persistent Pa infection was higher in MZ twins (0.589; 95% CI, 0.222-0.704) than in DZ twins (0.162; 95% CI, -0.352 to 0.607), generating a heritability of 0.85. CONCLUSION: Genetic modifiers play a significant role in the establishment and timing of persistent Pa infection in individuals with cystic fibrosis.


Assuntos
Fibrose Cística/genética , Doenças em Gêmeos/genética , Genes Modificadores/genética , Infecções por Pseudomonas/genética , Pseudomonas aeruginosa , Infecções Respiratórias/genética , Adolescente , Criança , Pré-Escolar , Fibrose Cística/microbiologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Epistasia Genética , Feminino , Humanos , Masculino , Infecções por Pseudomonas/complicações , Infecções Respiratórias/complicações , Gêmeos Dizigóticos , Gêmeos Monozigóticos
7.
PLoS One ; 6(11): e27784, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22125624

RESUMO

BACKGROUND: Progressive lung disease accounts for the majority of morbidity and mortality observed in cystic fibrosis (CF). Beyond secondhand smoke exposure and socio-economic status, the effect of specific environmental factors on CF lung function is largely unknown. METHODS: Multivariate regression was used to assess correlation between specific environmental factors, the presence of pulmonary pathogens, and variation in lung function using subjects enrolled in the U.S. CF Twin and Sibling Study (CFTSS: n = 1378). Significant associations were tested for replication in the U.S. CF Foundation Patient Registry (CFF: n = 16439), the Australian CF Data Registry (ACFDR: n = 1801), and prospectively ascertained subjects from Australia/New Zealand (ACFBAL: n = 167). RESULTS: In CFTSS subjects, the presence of Pseudomonas aeruginosa (OR = 1.06 per °F; p<0.001) was associated with warmer annual ambient temperatures. This finding was independently replicated in the CFF (1.02; p<0.001), ACFDR (1.05; p = 0.002), and ACFBAL (1.09; p = 0.003) subjects. Warmer temperatures (-0.34 points per °F; p = 0.005) and public insurance (-6.43 points; p<0.001) were associated with lower lung function in the CFTSS subjects. These findings were replicated in the CFF subjects (temperature: -0.31; p<0.001; insurance: -9.11; p<0.001) and similar in the ACFDR subjects (temperature: -0.23; p = 0.057). The association between temperature and lung function was minimally influenced by P. aeruginosa. Similarly, the association between temperature and P. aeruginosa was largely independent of lung function. CONCLUSIONS: Ambient temperature is associated with prevalence of P. aeruginosa and lung function in four independent samples of CF patients from two continents.


Assuntos
Infecções Bacterianas/fisiopatologia , Fibrose Cística/fisiopatologia , Pulmão/fisiopatologia , Temperatura Ambiente , Infecções Bacterianas/complicações , Complexo Burkholderia cepacia/isolamento & purificação , Estudos de Coortes , Fibrose Cística/complicações , Feminino , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Pulmão/microbiologia , Pulmão/patologia , Masculino , Pseudomonas aeruginosa/isolamento & purificação , Sistema de Registros/estatística & dados numéricos
8.
Respir Res ; 11: 140, 2010 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-20932301

RESUMO

BACKGROUND: Lung infection by various organisms is a characteristic feature of cystic fibrosis (CF). CFTR genotype effects acquisition of Pseudomonas aeruginosa (Pa), however the effect on acquisition of other infectious organisms that frequently precede Pa is relatively unknown. Understanding the role of CFTR in the acquisition of organisms first detected in patients may help guide symptomatic and molecular-based treatment for CF. METHODS: Lung infection, defined as a single positive respiratory tract culture, was assessed for 13 organisms in 1,381 individuals with CF. Subjects were divided by predicted CFTR function: 'Residual': carrying at least one partial function CFTR mutation (class IV or V) and 'Minimal' those who do not carry a partial function mutation. Kaplan-Meier estimates were created to assess CFTR effect on age of acquisition for each organism. Cox proportional hazard models were performed to control for possible cofactors. A separate Cox regression was used to determine whether defining infection with Pa, mucoid Pa or Aspergillus (Asp) using alternative criteria affected the results. The influence of severity of lung disease at the time of acquisition was evaluated using stratified Cox regression methods by lung disease categories. RESULTS: Subjects with 'Minimal' CFTR function had a higher hazard than patients with 'Residual' function for acquisition of 9 of 13 organisms studied (HR ranging from 1.7 to 3.78 based on the organism studied). Subjects with minimal CFTR function acquired infection at a younger age than those with residual function for 12 of 13 organisms (p-values ranging: < 0.001 to 0.017). Minimal CFTR function also associated with younger age of infection when 3 alternative definitions of infection with Pa, mucoid Pa or Asp were employed. Risk of infection is correlated with CFTR function for 8 of 9 organisms in patients with good lung function (>90%ile) but only 1 of 9 organisms in those with poorer lung function (<50%ile). CONCLUSIONS: Residual CFTR function correlates with later onset of respiratory tract infection by a wide spectrum of organisms frequently cultured from CF patients. The protective effect conferred by residual CFTR function is diminished in CF patients with more advanced lung disease.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/genética , Fibrose Cística/metabolismo , Mutação/genética , Infecções Respiratórias/genética , Adolescente , Adulto , Criança , Pré-Escolar , Fibrose Cística/microbiologia , Regulador de Condutância Transmembrana em Fibrose Cística/fisiologia , Feminino , Seguimentos , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/microbiologia , Adulto Jovem
9.
Am J Respir Crit Care Med ; 182(9): 1137-43, 2010 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-20581166

RESUMO

RATIONALE: Individuals with cystic fibrosis (CF) are subject to recurrent respiratory infections (exacerbations) that often require intravenous antibiotic treatment and may result in permanent loss of lung function. The optimal means of delivering therapy remains unclear. OBJECTIVES: To determine whether duration or venue of intravenous antibiotic administration affect lung function. METHODS: Data were retrospectively collected on 1,535 subjects recruited by the US CF Twin and Sibling Study from US CF care centers between 2000 and 2007. MEASUREMENTS AND MAIN RESULTS: Long-term decline in FEV1 after exacerbation was observed regardless of whether antibiotics were administered in the hospital (mean, -3.3 percentage points [95% confidence interval, -3.9 to -2.6]; n = 602 courses of therapy) or at home (mean, -3.5 percentage points [95% confidence interval, -4.5 to -2.5]; n = 232 courses of therapy); this decline was not different by venue using t tests (P = 0.69) or regression (P = 0.91). No difference in intervals between courses of antibiotics was observed between hospital (median, 119 d [interquartile range, 166]; n = 602) and home (median, 98 d [interquartile range, 155]; n = 232) (P = 0.29). Patients with greater drops in FEV1 with exacerbations had worse long-term decline even if lung function initially recovered with treatment (P < 0.001). Examination of FEV1 measures obtained during treatment for exacerbations indicated that improvement in FEV1 plateaus after 7-10 days of therapy. CONCLUSIONS: Intravenous antibiotic therapy for CF respiratory exacerbations administered in the hospital and in the home was found to be equivalent in terms of long-term FEV1 change and interval between courses of antibiotics. Optimal duration of therapy (7-10 d) may be shorter than current practice. Large prospective studies are needed to answer these essential questions for CF respiratory management.


Assuntos
Antibacterianos/administração & dosagem , Fibrose Cística/tratamento farmacológico , Hospitalização , Ambulatório Hospitalar , Adolescente , Assistência Ambulatorial , Criança , Fibrose Cística/fisiopatologia , Progressão da Doença , Feminino , Volume Expiratório Forçado , Humanos , Infusões Intravenosas , Tempo de Internação , Masculino , Recidiva , Estudos Retrospectivos , Resultado do Tratamento , Estados Unidos , Adulto Jovem
10.
J Cyst Fibros ; 9(2): 143-9, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20117062

RESUMO

BACKGROUND: The effectiveness of current treatment recommendations for vitamin D insufficiency in children with CF is unknown. Therefore, we assessed the effectiveness of vitamin D(2) 50,000 IU once daily for 28 days for vitamin D insufficiency. METHODS: Retrospective chart review of pediatric CF patients from 2006-2008. Vitamin D(2) 50,000 IU daily for 28 days was given to patients with 25-OHD <30 ng/mL and repeat 25-OHD levels were obtained after completion of therapy. RESULTS: One hundred forty-seven levels from 97 individuals were assessed. Success of treatment was 54% (n=80/147). Seventeen of 39 patients (43%) followed for an additional 6-18 months were able to maintain levels of >or=30 ng/mL. CONCLUSIONS: Vitamin D(2) 50,000 IU daily for 28 days was effective in correcting vitamin D insufficiency in approximately 50% of subjects. However, almost half of successfully treated patients were unable to maintain normal 25-OHD levels >6 months after completion of therapy, implying that this effect is transient.


Assuntos
Fibrose Cística/complicações , Ergocalciferóis/administração & dosagem , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/tratamento farmacológico , Vitaminas/administração & dosagem , 25-Hidroxivitamina D 2/sangue , Adolescente , Calcifediol/sangue , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Seguimentos , Humanos , Masculino , Prevalência , Estudos Retrospectivos , Estações do Ano , Fatores de Tempo , Resultado do Tratamento , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/epidemiologia
11.
Eur J Hum Genet ; 18(6): 680-4, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20068595

RESUMO

Variants in mannose-binding lectin (MBL2; protein MBL) have shown association with different aspects (eg, lung function, infection, survival) of cystic fibrosis (CF) in some studies but not others. Inconsistent results may be due to confounding among disease variables that were not fully accounted for in each study. To account for these relationships, we derived a modeling framework incorporating CFTR genotype, age, Pseudomonas aeruginosa (Pa) infection, and lung function from 788 patients in the US CF Twin and Sibling Study. This framework was then used to identify confounding variables when testing the effect of MBL2 variation on specific CF traits. MBL2 genotypes corresponding to low levels of MBL associated with Pa infection 1.94 years earlier than did MBL2 genotypes corresponding to high levels of MBL (P=0.0034). In addition, Pa-infected patients with MBL2 genotypes corresponding to low levels of MBL underwent conversion to mucoid Pa 2.72 years earlier than did patients with genotypes corresponding to high levels of MBL (P=0.0003). MBL2 was not associated with the time to transition from infection to conversion or with lung function. Thus, use of a modeling framework that identified confounding among disease variables revealed that variation in MBL2 associates with age at infection with Pa and age at conversion to mucoid Pa in CF.


Assuntos
Fibrose Cística/genética , Lectina de Ligação a Manose/genética , Modelos Genéticos , Adolescente , Adulto , Criança , Fibrose Cística/complicações , Feminino , Heterogeneidade Genética , Variação Genética/fisiologia , Humanos , Masculino , Lectina de Ligação a Manose/fisiologia , Modelos Biológicos , Infecções por Pseudomonas/complicações , Infecções por Pseudomonas/genética , Pseudomonas aeruginosa/fisiologia , Irmãos , Estudos em Gêmeos como Assunto , Gêmeos , Adulto Jovem
12.
Proc Natl Acad Sci U S A ; 100(3): 1010-5, 2003 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-12531921

RESUMO

For mRNA to be transported from the nucleus to the cytoplasm, it must travel from the site of transcription through the nuclear interior to the nuclear pore. Studies in Saccharomyces cerevisiae have suggested a relationship between poly(A) RNA trafficking and myosin-like protein 1 (Mlp1p), a nuclear-pore associated protein that is homologous to the mammalian Tpr (translocated promoter region) protein [Kosova, B., Panté, N., Rollenhagen, C., Podtelejnikov, A., Mann, M., Aebi, U., and Hurt, E. (2000) J. Biol. Chem. 275, 343-350]. We identified a yeast two-hybrid interaction between the C-terminal globular domain of Mlp1p and Nab2p, a shuttling heterogeneous nuclear ribonucleoprotein that is required for mRNA export. Coimmunoprecipitation confirms that Nab2p also interacts with full-length Mlp1p and in vitro binding experiments show that Nab2p binds directly to the C-terminal domain of Mlp1p. In addition, our experiments reveal that the C-terminal domain of Mlp1p is both necessary and sufficient to cause accumulation of poly(A) RNA and Nab2p in the nucleus. We propose a model where Mlp1p acts as a checkpoint at the nuclear pore by interacting with export-competent ribonucleoprotein complexes through its C-terminal globular domain. This study identifies Nab2p as a heterogeneous nuclear ribonucleoprotein found in complex with Mlp1p and begins to delineate the path that mRNA travels from the chromatin to the nuclear pore.


Assuntos
Proteínas de Membrana/química , Divisão Celular , Núcleo Celular/metabolismo , Galactose/metabolismo , Vetores Genéticos , Glucose/metabolismo , Glutationa Transferase/metabolismo , Proteínas de Fluorescência Verde , Hibridização in Situ Fluorescente , Proteínas Luminescentes/metabolismo , Poro Nuclear , Complexo de Proteínas Formadoras de Poros Nucleares , Proteínas Nucleares , Proteínas de Transporte Nucleocitoplasmático/química , Proteínas de Transporte Nucleocitoplasmático/metabolismo , Poli A/metabolismo , Testes de Precipitina , Ligação Proteica , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas/metabolismo , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/metabolismo , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/metabolismo , Técnicas do Sistema de Duplo-Híbrido
13.
J Biol Chem ; 278(9): 6731-40, 2003 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-12496292

RESUMO

Mature poly(A) RNA transcripts are exported from the nucleus in complex with heterogeneous nuclear ribonucleoproteins (hnRNPs). Nab2p is an essential Saccharomyces cerevisiae hnRNP protein that interacts with poly(A) RNA and shuttles between the nucleus and cytoplasm. Functional Nab2p is required for export of poly(A) RNA from the nucleus. The Nab2 protein consists of the following four domains: a unique N-terminal domain, a glutamine-rich domain, an arginine-glycine (RGG) domain, and a zinc finger domain. We generated Nab2p deletion mutants to analyze the contribution of each domain to the in vivo function of Nab2p. We first tested whether the deletion mutants could replace the essential NAB2 gene. We then examined the impact of these mutations on Nab2p localization, poly(A) RNA localization, and association of Nab2p with poly(A) RNA. Our analyses revealed that the N-terminal domain is required for nuclear export of both poly(A) RNA and Nab2p. We confirm that the RGG domain is important for Nab2p import in vivo. Finally, the zinc finger domain is critical for the interaction between Nab2p and poly(A) RNA in vivo. Our data support a model where Nab2p associates with poly(A) RNA in the nucleus through the zinc finger domain and facilitates the export of the poly(A) RNA through protein interactions mediated by the N-terminal domain.


Assuntos
Proteínas de Transporte Nucleocitoplasmático/química , Proteínas de Ligação a RNA/química , Proteínas de Saccharomyces cerevisiae/química , Saccharomyces cerevisiae/metabolismo , Alelos , Arginina/química , Núcleo Celular/metabolismo , Reagentes para Ligações Cruzadas/farmacologia , Citoplasma/metabolismo , Técnica Indireta de Fluorescência para Anticorpo , Deleção de Genes , Glutamina/química , Immunoblotting , Hibridização in Situ Fluorescente , Microscopia , Modelos Genéticos , Mutação , Proteínas de Transporte Nucleocitoplasmático/metabolismo , Plasmídeos/metabolismo , Poli A/metabolismo , Estrutura Terciária de Proteína , RNA/metabolismo , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Temperatura Ambiente , Dedos de Zinco
14.
J Biol Chem ; 277(10): 7752-60, 2002 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-11779864

RESUMO

From transcription to translation, mRNA is complexed with heterogeneous nuclear ribonucleoproteins (hnRNP proteins) that mediate mRNA processing, export from the nucleus, and delivery into the cytoplasm. Although the mechanism is unknown, export of mature mRNA from the nucleus is a critical regulatory step in gene expression. Analyses of hnRNP proteins have shown that many of these proteins are required for this essential cellular process. In this study, we characterize the Saccharomyces cerevisiae Nab2 protein, which was first identified as a poly(A) RNA-binding protein (Anderson, J. T., Wilson, S. M., Datar, K. V., and Swanson, M. S. (1993) Mol. Cell. Biol. 13, 2730-2741). Our work indicates that poly(A) RNA export from the nucleus is dependent upon a functional Nab2 protein; correspondingly, export of Nab2p from the nucleus is dependent upon ongoing RNA polymerase II transcription. Furthermore, we show that Nab2p is modified within its RGG domain by the type I protein-arginine methyltransferase, Hmt1p. Our experiments demonstrate that arginine methylation is required for the export of Nab2p from the nucleus and therefore establish an in vivo effect of this modification. Overall, these experiments provide evidence that Nab2p is an hnRNP protein that is required for poly(A) RNA export and whose export from the nucleus is regulated by Hmt1p.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Arginina/metabolismo , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/fisiologia , Proteínas de Transporte Nucleocitoplasmático , Poli A/metabolismo , Proteína-Arginina N-Metiltransferases , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/fisiologia , RNA/metabolismo , Proteínas Repressoras , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae/metabolismo , Sequência de Aminoácidos , Arginina/química , Núcleo Celular/metabolismo , Escherichia coli/metabolismo , Técnica Indireta de Fluorescência para Anticorpo , Deleção de Genes , Proteínas de Fluorescência Verde , Immunoblotting , Hibridização in Situ Fluorescente , Proteínas Luminescentes/metabolismo , Metilação , Dados de Sequência Molecular , Plasmídeos/metabolismo , Testes de Precipitina , Ligação Proteica , Biossíntese de Proteínas , Transporte Proteico , RNA Polimerase II/metabolismo , RNA Mensageiro/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Temperatura Ambiente , Transcrição Genética
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