Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 11 de 11
Filtrar
Más filtros












Base de datos
Intervalo de año de publicación
1.
Discov Med ; 36(186): 1334-1344, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-39054704

RESUMEN

N-acetyltransferase 10 (NAT10) is an important acetyltransferase that regulates telomerase activity and participates in DNA damage reactions, ribosomal RNA (rRNA) transcriptional activation, cell division, microtubule acetylation, and other important cellular processes. Abnormalities in the expression or distribution of NAT10 result in diseases such as Hutchinson-Gilford progeria syndrome (HGPS) and various tumors, with serious consequences. Remodelin, an inhibitor of NAT10, delays HGPS progression; many studies have been conducted on its role in tumor therapy. A major breakthrough in the study of NAT10 was the discovery of mRNA N4-acetylcytidine (ac4C) modification, which can increase mRNA stability and translation efficiency significantly. In addition, NAT10 modifies the mRNA of ac4C, which is associated with tumor development. Here, we present a review of pertinent studies focusing on NAT10, particularly its role in cancer, to provide researchers with a concise and informative summary of the current state of knowledge about this topic. The conclusions drawn from this review could provide a new direction for tumor treatment.


Asunto(s)
Neoplasias , Humanos , Neoplasias/patología , Neoplasias/genética , Neoplasias/enzimología , Acetiltransferasa E N-Terminal/metabolismo , Acetiltransferasa E N-Terminal/genética , Animales , Regulación Neoplásica de la Expresión Génica , Acetiltransferasas N-Terminal
2.
Cancer Med ; 13(11): e7283, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38826095

RESUMEN

BACKGROUND: Lung cancer remains the foremost reason of cancer-related mortality, with invasion and metastasis profoundly influencing patient prognosis. N-acetyltransferase 10 (NAT10) catalyzes the exclusive N (4)-acetylcytidine (ac4C) modification in eukaryotic RNA. NAT10 dysregulation is linked to various diseases, yet its role in non-small cell lung cancer (NSCLC) invasion and metastasis remains unclear. Our study delves into the clinical significance and functional aspects of NAT10 in NSCLC. METHODS: We investigated NAT10's clinical relevance using The Cancer Genome Atlas (TCGA) and a group of 98 NSCLC patients. Employing WB, qRT-PCR, and IHC analyses, we assessed NAT10 expression in NSCLC tissues, bronchial epithelial cells (BECs), NSCLC cell lines, and mouse xenografts. Further, knockdown and overexpression techniques (siRNA, shRNA, and plasmid) were employed to evaluate NAT10's effects. A series of assays were carried out, including CCK-8, colony formation, wound healing, and transwell assays, to elucidate NAT10's role in proliferation, invasion, and metastasis. Additionally, we utilized lung cancer patient-derived 3D organoids, mouse xenograft models, and Remodelin (NAT10 inhibitor) to corroborate these findings. RESULTS: Our investigations revealed high NAT10 expression in NSCLC tissues, cell lines and mouse xenograft models. High NAT10 level correlated with advanced T stage, lymph node metastasis and poor overall survive. NAT10 knockdown curtailed proliferation, invasion, and migration, whereas NAT10 overexpression yielded contrary effects. Furthermore, diminished NAT10 levels correlated with increased E-cadherin level whereas decreased N-cadherin and vimentin expressions, while heightened NAT10 expression displayed contrasting results. Notably, Remodelin efficiently attenuated NSCLC proliferation, invasion, and migration by inhibiting NAT10 through the epithelial-mesenchymal transition (EMT) pathway. CONCLUSIONS: Our data underscore NAT10 as a potential therapeutic target for NSCLC, presenting avenues for targeted intervention against lung cancer through NAT10 inhibition.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Proliferación Celular , Transición Epitelial-Mesenquimal , Neoplasias Pulmonares , Acetiltransferasa E N-Terminal , Humanos , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Animales , Ratones , Acetiltransferasa E N-Terminal/metabolismo , Acetiltransferasa E N-Terminal/genética , Masculino , Femenino , Progresión de la Enfermedad , Movimiento Celular , Regulación Neoplásica de la Expresión Génica , Línea Celular Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto , Ratones Desnudos , Persona de Mediana Edad , Acetiltransferasas N-Terminal
3.
Acta Pharmacol Sin ; 45(7): 1425-1437, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38839936

RESUMEN

Cardiac fibrosis is a pathological scarring process that impairs cardiac function. N-acetyltransferase 10 (Nat10) is recently identified as the key enzyme for the N4-acetylcytidine (ac4C) modification of mRNAs. In this study, we investigated the role of Nat10 in cardiac fibrosis following myocardial infarction (MI) and the related mechanisms. MI was induced in mice by ligation of the left anterior descending coronary artery; cardiac function was assessed with echocardiography. We showed that both the mRNA and protein expression levels of Nat10 were significantly increased in the infarct zone and border zone 4 weeks post-MI, and the expression of Nat10 in cardiac fibroblasts was significantly higher compared with that in cardiomyocytes after MI. Fibroblast-specific overexpression of Nat10 promoted collagen deposition and induced cardiac systolic dysfunction post-MI in mice. Conversely, fibroblast-specific knockout of Nat10 markedly relieved cardiac function impairment and extracellular matrix remodeling following MI. We then conducted ac4C-RNA binding protein immunoprecipitation-sequencing (RIP-seq) in cardiac fibroblasts transfected with Nat10 siRNA, and revealed that angiomotin-like 1 (Amotl1), an upstream regulator of the Hippo signaling pathway, was the target gene of Nat10. We demonstrated that Nat10-mediated ac4C modification of Amotl1 increased its mRNA stability and translation in neonatal cardiac fibroblasts, thereby increasing the interaction of Amotl1 with yes-associated protein 1 (Yap) and facilitating Yap translocation into the nucleus. Intriguingly, silencing of Amotl1 or Yap, as well as treatment with verteporfin, a selective and potent Yap inhibitor, attenuated the Nat10 overexpression-induced proliferation of cardiac fibroblasts and prevented their differentiation into myofibroblasts in vitro. In conclusion, this study highlights Nat10 as a crucial regulator of myocardial fibrosis following MI injury through ac4C modification of upstream activators within the Hippo/Yap signaling pathway.


Asunto(s)
Fibrosis , Ratones Endogámicos C57BL , Infarto del Miocardio , Animales , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Ratones , Masculino , Proteínas Señalizadoras YAP/metabolismo , Fibroblastos/metabolismo , Citidina/análogos & derivados , Citidina/farmacología , Ratones Noqueados , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Acetiltransferasa E N-Terminal/metabolismo , Vía de Señalización Hippo , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Células Cultivadas , Transducción de Señal , Acetiltransferasas N-Terminal/metabolismo , Miocardio/patología , Miocardio/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo
4.
Ann Agric Environ Med ; 31(2): 306-310, 2024 Jun 27.
Artículo en Inglés | MEDLINE | ID: mdl-38940118

RESUMEN

The NAA10 gene encodes N-alpha-acetyltransferase 10 which plays an important role in cell growth, differentiation, DNA damage, metastasis, apoptosis, stress response and autophagy. Defects in the NAA10 gene correlate with the diagnosis of NAA10-related syndrome (Ogden syndrome). The most common symptoms of NAA10-related syndrome are: global developmental delay, non-verbal or limited speech, autism spectrum disorder, feeding difficulties, motor delay, muscle tone disturbances, and long QT syndrome. To-date, there are about 100 patients who have been reported with this condition. The case report presents the clinical study of a girl aged 4 years and 3 months diagnosed with Ogden syndrome. She had many characteristic features of the disorder, as well as precocious puberty. This girl represents the case of a patient with p.Arg83Cys mutation in NAA10 gene as well as precocious puberty.


Asunto(s)
Acetiltransferasa A N-Terminal , Acetiltransferasa E N-Terminal , Pubertad Precoz , Humanos , Femenino , Pubertad Precoz/genética , Acetiltransferasa A N-Terminal/genética , Acetiltransferasa A N-Terminal/metabolismo , Acetiltransferasa E N-Terminal/genética , Acetiltransferasa E N-Terminal/metabolismo , Preescolar , Mutación
5.
PLoS One ; 19(5): e0301328, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38713657

RESUMEN

Amino-terminal (Nt-) acetylation (NTA) is a common protein modification, affecting approximately 80% of all human proteins. The human essential X-linked gene, NAA10, encodes for the enzyme NAA10, which is the catalytic subunit in the N-terminal acetyltransferase A (NatA) complex. There is extensive genetic variation in humans with missense, splice-site, and C-terminal frameshift variants in NAA10. In mice, Naa10 is not an essential gene, as there exists a paralogous gene, Naa12, that substantially rescues Naa10 knockout mice from embryonic lethality, whereas double knockouts (Naa10-/Y Naa12-/-) are embryonic lethal. However, the phenotypic variability in the mice is nonetheless quite extensive, including piebaldism, skeletal defects, small size, hydrocephaly, hydronephrosis, and neonatal lethality. Here we replicate these phenotypes with new genetic alleles in mice, but we demonstrate their modulation by genetic background and environmental effects. We cannot replicate a prior report of "maternal effect lethality" for heterozygous Naa10-/X female mice, but we do observe a small amount of embryonic lethality in the Naa10-/y male mice on the inbred genetic background in this different animal facility.


Asunto(s)
Ratones Noqueados , Acetiltransferasa A N-Terminal , Acetiltransferasa E N-Terminal , Animales , Acetiltransferasa A N-Terminal/genética , Acetiltransferasa A N-Terminal/metabolismo , Acetiltransferasa E N-Terminal/genética , Acetiltransferasa E N-Terminal/metabolismo , Ratones , Femenino , Masculino , Fenotipo , Antecedentes Genéticos , Herencia Materna/genética , Ratones Endogámicos C57BL
6.
Am J Med Genet A ; 194(9): e63651, 2024 09.
Artículo en Inglés | MEDLINE | ID: mdl-38747166

RESUMEN

Ogden syndrome, also known as NAA10-related neurodevelopmental syndrome, is a rare genetic condition associated with pathogenic variants in the NAA10 N-terminal acetylation family of proteins. The condition was initially described in 2011 and is characterized by a range of neurologic symptoms, including intellectual disability and seizures, as well as developmental delays, psychiatric symptoms, congenital heart abnormalities, hypotonia, and others. Previously published articles have described the etiology and phenotype of Ogden syndrome, mostly with retrospective analyses; herein, we report prospective data concerning its progress over time. The current study involves a total of 58 distinct participants; of these, 43 caregivers were interviewed using the Vineland-3 and answered a survey regarding therapy and other questions, 10 of whom completed the Vineland-3 but did not answer the survey, and 5 participants who answered the survey but have not yet performed the Vineland-3 due to language constraints. The average age at the time of the most recent assessment was 12.4 years, with individuals ranging in age from 11 months to 40.2 years. Using Vineland-3 scores, we show decline in cognitive function over time in individuals with Ogden syndrome (n = 53). Sub-domain analysis found the decline to be present across all modalities. In addition, we describe the nature of seizures in this condition in greater detail, as well as investigate how already-available non-pharmaceutical therapies impact individuals with NAA10-related neurodevelopmental syndrome. Additional investigation between seizure and non-seizure groups showed no significant difference in adaptive behavior outcomes. A therapy investigation showed speech therapy to be the most commonly used therapy by individuals with NAA10-related neurodevelopmental syndrome, followed by occupational and physical therapy, with more severely affected individuals receiving more types of therapy than their less-severe counterparts. Early intervention analysis was only significantly effective for speech therapy, with analyses of all other therapies being non-significant. Our study portrays the decline in cognitive function over time of individuals within our cohort, independent of seizure status, and therapies being received, and highlights the urgent need for the development of effective treatments for Ogden syndrome.


Asunto(s)
Convulsiones , Humanos , Convulsiones/genética , Convulsiones/fisiopatología , Convulsiones/terapia , Femenino , Masculino , Niño , Preescolar , Adulto , Lactante , Adolescente , Discapacidad Intelectual/genética , Adulto Joven , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/terapia , Acetiltransferasa E N-Terminal/genética , Acetiltransferasa A N-Terminal/genética , Fenotipo
7.
Curr Opin Genet Dev ; 87: 102207, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38820741

RESUMEN

N4-acetylcytidine (ac4C) is an RNA modification that is catalyzed by the enzyme NAT10. Constitutively found in tRNA and rRNA, ac4C displays a dynamic presence in mRNA that is shaped by developmental and induced shifts in NAT10 levels. However, deciphering ac4C functions in mRNA has been hampered by its context-dependent influences in translation and the complexity of isolating effects on specific mRNAs from other NAT10 activities. Recent advances have begun to overcome these obstacles by leveraging natural variations in mRNA acetylation in cancer, developmental transitions, and immune responses. Here, we synthesize the current literature with a focus on nuances that may fuel the perception of cellular discrepancies toward the development of a cohesive model of ac4C function in mRNA.


Asunto(s)
Citidina , ARN Mensajero , Humanos , Acetilación , Citidina/análogos & derivados , Citidina/metabolismo , Citidina/genética , Acetiltransferasa E N-Terminal/genética , Acetiltransferasa E N-Terminal/metabolismo , Acetiltransferasas N-Terminal , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo
8.
Plant Physiol ; 195(4): 3097-3118, 2024 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-38588051

RESUMEN

In humans and plants, 40% of the proteome is cotranslationally acetylated at the N-terminus by a single Nα-acetyltransferase (Nat) termed NatA. The core NatA complex is comprised of the catalytic subunit Nα-acetyltransferase 10 (NAA10) and the ribosome-anchoring subunit NAA15. The regulatory subunit Huntingtin Yeast Partner K (HYPK) and the acetyltransferase NAA50 join this complex in humans. Even though both are conserved in Arabidopsis (Arabidopsis thaliana), only AtHYPK is known to interact with AtNatA. Here we uncover the AtNAA50 interactome and provide evidence for the association of AtNAA50 with NatA at ribosomes. In agreement with the latter, a split-luciferase approach demonstrated close proximity of AtNAA50 and AtNatA in planta. Despite their interaction, AtNatA/HYPK and AtNAA50 exerted different functions in vivo. Unlike NatA/HYPK, AtNAA50 did not modulate drought tolerance or promote protein stability. Instead, transcriptome and proteome analyses of a novel AtNAA50-depleted mutant (amiNAA50) implied that AtNAA50 negatively regulates plant immunity. Indeed, amiNAA50 plants exhibited enhanced resistance to oomycetes and bacterial pathogens. In contrast to what was observed in NatA-depleted mutants, this resistance was independent of an accumulation of salicylic acid prior to pathogen exposure. Our study dissects the in vivo function of the NatA interactors HYPK and NAA50 and uncovers NatA-independent roles for NAA50 in plants.


Asunto(s)
Acetiltransferasas , Proteínas de Arabidopsis , Arabidopsis , Acetiltransferasa E N-Terminal , Inmunidad de la Planta , Acetiltransferasas/metabolismo , Acetiltransferasas/genética , Arabidopsis/genética , Arabidopsis/inmunología , Arabidopsis/microbiología , Arabidopsis/metabolismo , Arabidopsis/enzimología , Proteínas de Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Regulación de la Expresión Génica de las Plantas , Acetiltransferasa A N-Terminal/metabolismo , Acetiltransferasa A N-Terminal/genética , Enfermedades de las Plantas/microbiología , Enfermedades de las Plantas/inmunología , Enfermedades de las Plantas/genética , Inmunidad de la Planta/genética , Pseudomonas syringae/fisiología , Pseudomonas syringae/patogenicidad , Ácido Salicílico/metabolismo , Acetiltransferasa E N-Terminal/genética , Acetiltransferasa E N-Terminal/metabolismo
9.
Pathol Res Pract ; 255: 155191, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38340582

RESUMEN

INTRODUCTION: We aimed to investigate the expression and prognostic role of NAA10 in clear cell renal cell carcinoma (ccRCC). MATERIAL AND METHODS: We performed a gene expression and survival analysis based on the human cancer genome atlas database of ccRCC patients (TCGA-KIRC). RESULTS: The patients in the TCGA-KIRC (n = 537) were divided into two subgroups: NAA10-low and NAA10-high expression groups. NAA10-high ccRCC exhibited higher T stages (p = 0.002), a higher frequency of distant metastasis (p = 0.018), more advanced AJCC stages (p < 0.001), a lower overall survival time (p = 0.036), and a lower survival rate (p < 0.001). NAA10-high ccRCC was associated with increased activity of non-specific oncogenic pathways, including oxidative phosphorylation (p < 0.001) and cell cycle progression [G2 to M phase transition (p = 0.045) and E2F targets (p < 0.001)]. Additionally, the NAA10-high tumors showed reduced apoptosis via TRIAL pathways (p < 0.001) and increased levels of activity that promoted epithelial-mesenchymal transition (p = 0.026) or undifferentiation (p = 0.01). In ccRCC, NAA10 expression was found to be a negative prognostic factor in both non-metastatic (p < 0.001) and metastatic tumors (p = 0.032). CONCLUSIONS: In ccRCC, NAA10 expression was shown to be a negative prognostic factor related to tumor progression rather than tumor initiation, and high NAA10 expression promoted epithelial-mesenchymal transition and undifferentiation.


Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/patología , Neoplasias Renales/patología , Pronóstico , Transición Epitelial-Mesenquimal/genética , Expresión Génica , Acetiltransferasa A N-Terminal/genética , Acetiltransferasa E N-Terminal/genética
10.
Medicine (Baltimore) ; 103(6): e36034, 2024 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-38335407

RESUMEN

RATIONALE: Ogden syndrome is an exceptionally rare X-linked disease caused by mutations in the NAA10 gene. Reported cases of this syndrome are approximately 20 children and are associated with facial dysmorphism, growth delay, developmental disorders, congenital heart disease, and arrhythmia. PATIENT CONCERNS: We present the clinical profile of a 3-year-old girl with Ogden syndrome carrying a de novo NAA10 variant [NM_003491:c.247C>T, p.(Arg83Cys)]. During infancy, she exhibited features such as left ventricular hypertrophy, protruding eyeballs, and facial deformities. DIAGNOSIS: Clinical diagnosis included Ogden syndrome, congenital heart disease (obstructive hypertrophic cardiomyopathy, left ventricular outflow tract obstruction, mitral valve disease, tricuspid valve regurgitation), tonsillar and adenoidal hypertrophy, and speech and language delay. INTERVENTIONS: The girl was considered to have hypertrophic cardiomyopathy (HCM) and received oral metoprolol as a treatment for HCM at our hospital. The drug treatment effect was not ideal, and her hypertrophy myocardial symptoms were aggravated and she had to be hospitalized for surgery. OUTCOMES: The girl underwent a modified Morrow procedure under cardiopulmonary bypass and experienced a favorable postoperative recovery. No pulmonary infections or significant complications were observed during this period. The patient's family expressed satisfaction with the treatment process. LESSONS: The case emphasizes the HCM of Odgen syndrome, and early surgery should be performed if drug treatment is ineffective.


Asunto(s)
Cardiomiopatía Hipertrófica , Cardiopatías Congénitas , Humanos , Femenino , Niño , Preescolar , Cardiomiopatía Hipertrófica/complicaciones , Cardiomiopatía Hipertrófica/genética , Cardiomiopatía Hipertrófica/diagnóstico , Válvula Mitral , Miocardio , Cardiopatías Congénitas/complicaciones , Cardiopatías Congénitas/genética , Hipertrofia , Acetiltransferasa A N-Terminal , Acetiltransferasa E N-Terminal
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...