RESUMEN
Imaging modalities for percutaneous coronary intervention (PCI), such as intravascular ultrasound (IVUS) or optical coherence tomography (OCT), have increased in the current PCI era. However, their clinical benefits in acute myocardial infarction (AMI) have not been fully elucidated. This study investigated the long-term outcomes of image-guided PCI in patients with AMI using data from the Korean Acute Myocardial Infarction Registry. A total of 9,271 patients with AMI, who underwent PCI with second-generation drug-eluting stents between November 2011 and December 2015, were retrospectively examined, and target lesion failure (TLF) at 3 years (defined as the composite of cardiac death, target vessel myocardial infarction, and ischemia-driven target lesion revascularization) was evaluated. From the registry, 2,134 patients (23.0%) underwent image-guided PCI (IVUS-guided: n = 1,919 [20.6%]; OCT-guided: n = 215 patients [2.3%]). Based on propensity score matching, image-guided PCI was associated with a significant reduction in TLF (hazard ratio: 0.76; 95% confidence interval: 0.59-0.98, p = 0.035). In addition, the TLF incidence in the OCT-guided PCI group was comparable to that in the IVUS-guided PCI group (5.3% vs 4.7%, p = 0.903). Image-guided PCI, including IVUS and OCT, is associated with favorable clinical outcomes in patients with AMI at 3 years post-intervention. Additionally, OCT-guided PCI is not inferior to IVUS-guided PCI in patients with AMI.
Asunto(s)
Infarto del Miocardio , Intervención Coronaria Percutánea , Sistema de Registros , Tomografía de Coherencia Óptica , Humanos , Intervención Coronaria Percutánea/métodos , Masculino , Femenino , República de Corea/epidemiología , Infarto del Miocardio/diagnóstico por imagen , Infarto del Miocardio/terapia , Infarto del Miocardio/cirugía , Persona de Mediana Edad , Anciano , Resultado del Tratamiento , Tomografía de Coherencia Óptica/métodos , Estudios Retrospectivos , Ultrasonografía Intervencional/métodos , Stents Liberadores de Fármacos , Cirugía Asistida por Computador/métodosRESUMEN
INTRODUCTION: A high percentage of patients with gallstones exhibit abnormalities in gallbladder emptying, and gallstones are often associated with gallbladder contraction. Interstitial cells of Cajal (ICC) in the gallbladder are involved in the generation and spreading of spontaneous contractions of the gallbladder. This study examined the relationship among the number of gallbladder ICC, gallbladder contractility, and gallstones. MATERIALS AND METHODS: Forty-six patients, who underwent cholecystectomy within 3 months of enduring a gallbladder ejection fraction scan, were enrolled in this study. ICC were identified using a microscope after immunohistochemical staining for CD117/c-kit. Five high-power field (magnification 400×) units were randomly assigned, and the number of ICC in the mucosal and muscular layers was counted. These counts were compared according to the sex, age, reason for cholecystectomy, presence of gallstone, presence of gallbladder polyp, gallbladder ejection fraction, and gallbladder size for each patient. RESULTS: The number of ICC in the mucosal layer was increased in the male participants (154.4 ± 73.9) compared with the female participants (107.3 ± 75.2); however, the ICC in the muscular layer was not different between the 2 groups. Additionally, the ICC in the mucosal and muscular layers did not differ according to age, cause of cholecystectomy, number of stones, stone character, stone diameter, or the presence of polyps. A larger gallbladder size was correlated with a decreased number of ICC in the muscular layer of the gallbladder. Additionally, when the number of gallbladder stones was increased, the number of ICC in the muscular layer of the gallbladder was decreased; however, there was no significant correlation between the number of ICC in the mucosal layer of the gallbladder and any of the following factors: age, GBEF, gallbladder size, stone number, or diameter. Furthermore, there was no significant correlation between the number of ICC in the muscular layer of the gallbladder, regardless of age, GBEF, and stone diameter. CONCLUSION: Although we were unable to achieve significant results regarding the relationship between GBEF and ICC, this is the first human study to reveal the relationship among ICC, gallbladder size, and the number of gallstones.
Asunto(s)
Cálculos Biliares , Células Intersticiales de Cajal , Colecistectomía , Femenino , Vesícula Biliar , Vaciamiento Vesicular , Humanos , MasculinoRESUMEN
BACKGROUND: Midface concavity is a relatively common facial feature in East Asian populations. Paranasal augmentation is becoming an increasingly popular procedure for patients with mild concavity and normal occlusion. In this study, we evaluate clinical outcomes following a series of paranasal augmentation. METHODS: A retrospective review was performed for patients with Class I occlusion who had undergone bilateral paranasal augmentation using custom-made silicone implants, between October 2005 and September 2013. Patient charts were reviewed for demographic information, concomitant operations, and postoperative complications. Preoperative and postoperative (1-month) photographs were used to evaluate operative outcome. RESULTS: The review identified a total of 93 patients meeting study criteria. Overall, aesthetic outcomes were satisfactory. Five-millimeter thick silicone implant was used in 81 cases, and the mean augmentation was 4.26 mm for this thickness. Among the 93 patients, 2 patients required immediate implant removal due to discomfort. An additional 3 patients experienced implant migration without any extrusion. Nine patients complained of transient paresthesia, which had resolved by 2 weeks. There were no cases of hematoma or infection. All patients reported improvement in their lateral profile and were pleased at follow-up. Complications that arose postoperatively included 9 cases of numbness in the upper lip and 3 cases of implant migration. All cases yielded satisfactory results without persisting complications. Sensations were fully restored postoperatively after 1 to 2 weeks. CONCLUSION: Paranasal augmentation with custom-made silicone implants is a simple, safe, and inexpensive method that can readily improve the lateral profile of a patient with normal occlusion. When combined with other aesthetic procedures, paranasal augmentation can synergistically improve outcome and lead to greater patient satisfaction.
RESUMEN
BACKGROUND: Although botulinum toxin type A has been shown to inhibit the formation of hypertrophic scars, little is known about the underlying mechanisms of action. Studies have reported that botulinum toxin type A is able to inhibit fibroblast proliferation and transforming growth factor (TGF)-ß1 expression; therefore, in this study, the authors evaluated its effect on the differentiation of fibroblasts derived from normal and hypertrophic scar tissue. METHODS: Under local anesthesia, tissue specimens from 10 scars (five normal mature scars and five hypertrophic scars) were obtained from nine patients who visited the authors' department for scar revision. Fibroblasts isolated from the tissue specimens were cultured until confluent and pretreated with TGF-ß1 to induce differentiation before treatment with botulinum toxin type A. Expression of the myofibroblast marker α-smooth muscle actin in cell cultures was evaluated by enzyme-linked immunosorbent assay and quantitative reverse transcription polymerase chain reaction. Fibroblast-to-myofibroblast differentiation was further evaluated by immunocytochemistry and confocal microscopy. RESULTS: The authors' results showed that α-smooth muscle actin mRNA and protein levels were significantly lower in the botulinum toxin type A-treated group than in the control group (treated with TGF-ß1 only) of fibroblasts derived from hypertrophic scars, but not fibroblasts derived from normal scars. Immunocytochemistry results also showed that fibroblast-to-myofibroblast differentiation was significantly decreased after botulinum toxin type A treatment in fibroblasts derived from hypertrophic scars. CONCLUSION: The authors' results show that botulinum toxin type A directly inhibits fibroblast-to-myofibroblast differentiation in vitro, and indicate its potential for use in treating wounds expected to develop into hypertrophic scars after trauma, burn, or surgery. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.
Asunto(s)
Toxinas Botulínicas Tipo A/farmacología , Diferenciación Celular/efectos de los fármacos , Cicatriz Hipertrófica/tratamiento farmacológico , Cicatriz Hipertrófica/patología , Miofibroblastos/efectos de los fármacos , Análisis de Varianza , Biopsia con Aguja , Estudios de Casos y Controles , Diferenciación Celular/fisiología , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Ensayo de Inmunoadsorción Enzimática , Femenino , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Humanos , Inmunohistoquímica , Masculino , Miofibroblastos/citología , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Valores de Referencia , Muestreo , Técnicas de Cultivo de TejidosRESUMEN
Mucin hypersecretion and overproduction are frequent manifestations of respiratory disease. Determining the physiological function of airway mucin is presently considered more important than identifying the relevant signaling pathways. The lack of a full-length human mucin 8 (MUC8) cDNA sequence has hindered the generation of a Muc8 knockout mouse line. Thus, the precise physiological functions of MUC8 are unclear. Herein, we investigated the function of MUC8 using a small-interfering RNA (siRNA)-mediated genetic silencing approach in human airway epithelial cells. Herein, intracellular IL-1α production was stimulated by an ATP/P2Y2 complex. While ATP/P2Y2 increased IL-1α secretion in a time-dependent manner, treatment with P2Y2-specific siRNA significantly decreased IL-1α secretion. Moreover, ATP increased P2Y2-mediated upregulation of MUC8 expression; however, IL-1α significantly decreased the extent to which ATP/P2Y2 upregulated MUC8 expression. Interestingly, treatment with MUC8-specific siRNA decreased the production of anti-inflammatory cytokines (TGF-ß and IL-1 receptor antagonist) and increased the production of inflammatory cytokines (IL-1α and IL-6) in our system. In addition, siRNA-mediated knockdown of MUC8 expression dramatically increased the secretion of inflammatory chemokines and resulted in an approximately threefold decrease in cell chemotaxis. We propose that MUC8 may function as an anti-inflammatory mucin that participates in inflammatory response by attracting immune cells/cytokines to the site of inflammation. Our results provide new insight into the physiological function of MUC8 and enhance our understanding of mucin overproduction during airway inflammation.
Asunto(s)
Adenosina Trifosfato/metabolismo , Silenciador del Gen , Mucinas/biosíntesis , ARN Interferente Pequeño , Receptores Purinérgicos P2Y2/metabolismo , Enfermedades Respiratorias/metabolismo , Animales , Línea Celular Tumoral , Humanos , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Proteína Antagonista del Receptor de Interleucina 1/genética , Proteína Antagonista del Receptor de Interleucina 1/metabolismo , Interleucina-1alfa/genética , Interleucina-1alfa/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Ratones , Ratones Noqueados , Mucinas/genética , Receptores Purinérgicos P2Y2/genética , Enfermedades Respiratorias/genética , Enfermedades Respiratorias/patología , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Glycogen synthase kinase 3ß (GSK3ß) participates in many cellular processes, and its dysregulation has been implicated in a wide range of diseases such as obesity, type 2 diabetes, cancer, and Alzheimer disease. Inactivation of GSK3ß by phosphorylation at specific residues is a primary mechanism by which this constitutively active kinase is controlled. However, the regulatory mechanism of GSK3ß is not fully understood. Dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) has multiple biological functions that occur as the result of phosphorylation of diverse proteins that are involved in metabolism, synaptic function, and neurodegeneration. Here we show that GSK3ß directly interacts with and is phosphorylated by Dyrk1A. Dyrk1A-mediated phosphorylation at the Thr(356) residue inhibits GSK3ß activity. Dyrk1A transgenic (TG) mice are lean and resistant to diet-induced obesity because of reduced fat mass, which shows an inverse correlation with the effect of GSK3ß on obesity. This result suggests a potential in vivo association between GSK3ß and Dyrk1A regarding the mechanism underlying obesity. The level of Thr(P)(356)-GSK3ß was higher in the white adipose tissue of Dyrk1A TG mice compared with control mice. GSK3ß activity was differentially regulated by phosphorylation at different sites in adipose tissue depending on the type of diet the mice were fed. Furthermore, overexpression of Dyrk1A suppressed the expression of adipogenic proteins, including peroxisome proliferator-activated receptor γ, in 3T3-L1 cells and in young Dyrk1A TG mice fed a chow diet. Taken together, these results reveal a novel regulatory mechanism for GSK3ß activity and indicate that overexpression of Dyrk1A may contribute to the obesity-resistant phenotype through phosphorylation and inactivation of GSK3ß.
Asunto(s)
Regulación Enzimológica de la Expresión Génica , Glucógeno Sintasa Quinasa 3/metabolismo , Obesidad/enzimología , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Células 3T3-L1 , Tejido Adiposo/metabolismo , Animales , Diferenciación Celular , Modelos Animales de Enfermedad , Glucógeno Sintasa Quinasa 3 beta , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Obesidad/tratamiento farmacológico , Fenotipo , Fosforilación , ARN Interferente Pequeño/metabolismo , Treonina/química , Quinasas DyrKRESUMEN
BACKGROUND: In Asia, one of the most important factors in being physically attractive is to have aesthetically pleasing legs, which has made calf contouring surgery an issue nowadays. When one leg is abnormally changed because of various factors (e.g., iatrogenic causes, poliomyelitis, cerebral palsy, trauma, and tumor resection), the tissue atrophies. Such asymmetric calves can be corrected by various surgical methods. METHODS: Calf asymmetry is defined as a difference in the maximal circumference greater than 2.0 cm between both calves. From 2005 to 2012, the authors carried out calf contouring operations on 68 patients. For patients with mild or moderate asymmetry, selective neurectomy with or without liposuction was performed on the hypertrophic calf according to shape and severity. For patients with severe asymmetry, selective neurectomy with liposuction was performed for the hypertrophic calf, whereas the hypotrophic calf was treated with fat injection or silicone implantation. RESULTS: At a minimum of 3 months' follow-up, the mild group patients had a size difference less than 0.5 cm. The moderate and severe asymmetry groups showed size differences less than 1.2 and 2.3 cm, respectively. No functional problems or major complications were shown. Minor complications included five cases of wound dehiscence, three cases of hematoma, and six cases of hypertrophic scar at the incision site. CONCLUSION: Classifying patients into three groups according to the maximal circumferential difference between both legs and treating them separately using different surgical methods could significantly provide satisfying outcomes in both functional and aesthetic aspects. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.
Asunto(s)
Pueblo Asiatico , Extremidad Inferior/cirugía , Músculo Esquelético/cirugía , Cirugía Plástica/métodos , Adulto , Estudios de Cohortes , Estética , Femenino , Humanos , Hipertrofia/clasificación , Hipertrofia/cirugía , Lipectomía/métodos , Masculino , Persona de Mediana Edad , Músculo Esquelético/patología , Atrofia Muscular/clasificación , Atrofia Muscular/cirugía , Prótesis e Implantes , República de Corea , Medición de Riesgo , Resultado del Tratamiento , Adulto JovenRESUMEN
After restoration of orbit wall fracture, preventing sequelae is important. An absorbable mesh is commonly used in orbit wall fracture, yet it has limitation due to orbit sagging when bony defect is larger than the moderate size (1 × 1 cm2). In this study, the authors present a satisfactory result in treating orbit wall fracture larger than the moderate size with a combination of absorbable mesh and demineralized bone matrix.From 2009 to 2012, 63 patients with bony defect larger than the moderate size, who were treated with a combination of absorbable mesh and demineralized bone matrix, were reviewed retrospectively. The site of bony defect, size, and applied amount of demineralized bone matrix were reviewed, and a 2-year follow-up was done. Facial computed tomography scans were checked preoperative, immediate postoperative, and 2-year postoperative.Among the 63 patients, there were 52 men and 11 women. Mean age was 33.3 years. The most common cause was blunt blow (35 cases); mean defect size was 13.36 × 12.82 mm2 in inferior wall fracture and 20.69 × 14.41 mm2 in medial wall fracture. There was no complication except for 3 cases of infraorbital nerve hypoesthesia. A 2-year follow-up computed tomography showed that the surgical site preserved bony formation without herniation. In treating moderate-sized bony defect in orbit wall fracture, absorbable mesh and demineralized bone matrix can maintain structural stability through good bony formation even after degradation of absorbable mesh.
Asunto(s)
Implantes Absorbibles , Técnica de Desmineralización de Huesos , Matriz Ósea , Hernia/prevención & control , Enfermedades Orbitales/prevención & control , Fracturas Orbitales/cirugía , Mallas Quirúrgicas , Adulto , Femenino , Humanos , Masculino , Órbita/cirugía , Complicaciones Posoperatorias/prevención & control , Estudios Retrospectivos , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Cephalometric analysis is essential for planning treatment in maxillofacial and aesthetic facial surgery. Although photometric analysis of the Korean nose has been attempted in the past, anthropometry of the deeper nasal structures in the same population based on computerized tomography (CT) has not been published. We therefore measured three anthropometric parameters of the nose on CT scans in our clinical series of patients. METHODS: We conducted the current retrospective study of a total of 100 patients (n=100) who underwent a CT-guided radiological measurement at our institution during a period ranging from January of 2008 to August of 2010. In these patients, we took three anthropometric measurements: the nasofrontal angle, the pyramidal angle, and the linear distance between the nasion and the tip of the nasal bone. RESULTS: The mean nasofrontal angle was 131.14° in the male patients and 140.70° in the female patients. The mean linear distance between the nasion and the tip of the nasal bone was 21.28 mm and 18.02 mm, respectively. The mean nasal pyramidal angle was 112.89° and 103.25° at the level of the nasal root, 117.49° and 115.60° at the middle level of the nasal bone, and 127.99° and 125.04° at the level of the tip of the nasal bone, respectively. CONCLUSIONS: In conclusion, our data will be helpful in the preparation of silicone implants for augmentation and/or corrective rhinoplasty in ethnic Korean people.
RESUMEN
Feeding behavior is one of the most essential activities in animals, which is tightly regulated by neuroendocrine factors. Drosophila melanogaster short neuropeptide F (sNPF) and the mammalian functional homolog neuropeptide Y (NPY) regulate food intake. Understanding the molecular mechanism of sNPF and NPY signaling is critical to elucidate feeding regulation. Here, we found that minibrain (mnb) and the mammalian ortholog Dyrk1a, target genes of sNPF and NPY signaling, [corrected] regulate food intake in Drosophila melanogaster and mice. In Drosophila melanogaster neuronal cells and mouse hypothalamic cells, sNPF and NPY modulated the mnb and Dyrk1a expression through the PKA-CREB pathway. Increased Dyrk1a activated Sirt1 to regulate the deacetylation of FOXO, which potentiated FOXO-induced sNPF/NPY expression and in turn promoted food intake. Conversely, AKT-mediated insulin signaling suppressed FOXO-mediated sNPF/NPY expression, which resulted in decreasing food intake. Furthermore, human Dyrk1a transgenic mice exhibited decreased FOXO acetylation and increased NPY expression in the hypothalamus, and [corrected] increased food intake. Our findings demonstrate that Mnb/Dyrk1a regulates food intake through the evolutionary conserved Sir2-FOXO-sNPF/NPY pathway in Drosophila melanogaster and mammals.
Asunto(s)
Regulación del Apetito/genética , Ingestión de Alimentos/fisiología , Conducta Alimentaria/fisiología , Regulación de la Expresión Génica , Transducción de Señal/genética , Acetilación , Animales , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/fisiología , Proteína Forkhead Box O1 , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Humanos , Hipotálamo/fisiología , Mamíferos/fisiología , Ratones , Neuropéptido Y/genética , Neuropéptido Y/metabolismo , Neuropéptidos/genética , Neuropéptidos/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas/metabolismo , Sirtuina 1/genética , Sirtuina 1/metabolismo , Quinasas DyrKRESUMEN
Dual-specificity tyrosine(Y)-phosphorylation-regulated kinase 1A (Dyrk1A) is a protein kinase that might be responsible for mental retardation and early onset of Alzheimer's disease in Down's syndrome patients. Dyrk1A plays a role in many cellular pathways through phosphorylation of diverse substrate proteins; however, its role in synaptic vesicle exocytosis is poorly understood. Munc18-1, a central regulator of neurotransmitter release, interacts with Syntaxin 1 and X11α. Syntaxin 1 is a key soluble N-ethylmaleimide-sensitive factor attachment protein receptor protein involved in synaptic vesicle docking/fusion events, and X11α modulates amyloid precursor protein processing and ß amyloid generation. In this study, we demonstrate that Dyrk1A interacts with and phosphorylates Munc18-1 at the Thr(479) residue. The phosphorylation of Munc18-1 at Thr(479) by Dyrk1A stimulated binding of Munc18-1 to Syntaxin 1 and X11α. Furthermore, the levels of phospho-Thr(479) -Munc18-1 were enhanced in the brains of transgenic mice over-expressing Dyrk1A protein, providing in vivo evidence of Munc18-1 phosphorylation by Dyrk1A. These results reveal a link between Munc18-1 and Dyrk1A in synaptic vesicle trafficking and amyloid precursor protein processing, suggesting that up-regulated Dyrk1A in Down's syndrome and Alzheimer's disease brains may contribute to some pathological features, including synaptic dysfunction and cognitive defect through abnormal phosphorylation of Munc18-1.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Munc18/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Sintaxina 1/metabolismo , Adenosina Trifosfato/farmacocinética , Animales , Encéfalo/metabolismo , Línea Celular Transformada , Humanos , Inmunoprecipitación , Ratones , Ratones Noqueados , Proteínas Munc18/deficiencia , Proteínas Munc18/genética , Mutación/fisiología , Isótopos de Fósforo/farmacocinética , Fosforilación/genética , Unión Proteica/efectos de los fármacos , Unión Proteica/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/farmacología , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas/farmacología , Treonina/metabolismo , Transfección , Quinasas DyrKRESUMEN
With the gradual increase of cases using fillers, cases of patients treated by non-medical professionals or inexperienced physicians resulting in complications are also increasing. We herein report 2 patients who experienced acute complications after receiving filler injections and were successfully treated with adipose-derived stem cell (ADSCs) therapy. Case 1 was a 23-year-old female patient who received a filler (Restylane) injection in her forehead, glabella, and nose by a non-medical professional. The day after her injection, inflammation was observed with a 3×3 cm skin necrosis. Case 2 was a 30-year-old woman who received a filler injection of hyaluronic acid gel (Juvederm) on her nasal dorsum and tip at a private clinic. She developed erythema and swelling in the filler-injected area A solution containing ADSCs harvested from each patient's abdominal subcutaneous tissue was injected into the lesion at the subcutaneous and dermis levels. The wounds healed without additional treatment. With continuous follow-up, both patients experienced only fine linear scars 6 months postoperatively. By using adipose-derived stem cells, we successfully treated the acute complications of skin necrosis after the filler injection, resulting in much less scarring, and more satisfactory results were achieved not only in wound healing, but also in esthetics.
RESUMEN
Two genes on chromosome 21, namely dual specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) and regulator of calcineurin 1 (RCAN1), have been implicated in some of the phenotypic characteristics of Down syndrome, including the early onset of Alzheimer disease. Although a link between Dyrk1A and RCAN1 and the nuclear factor of activated T cells (NFAT) pathway has been reported, it remains unclear whether Dyrk1A directly interacts with RCAN1. In the present study, Dyrk1A is shown to directly interact with and phosphorylate RCAN1 at Ser(112) and Thr(192) residues. Dyrk1A-mediated phosphorylation of RCAN1 at Ser(112) primes the protein for the GSK3ß-mediated phosphorylation of Ser(108). Phosphorylation of RCAN1 at Thr(192) by Dyrk1A enhances the ability of RCAN1 to inhibit the phosphatase activity of calcineurin (Caln), leading to reduced NFAT transcriptional activity and enhanced Tau phosphorylation. These effects are mediated by the enhanced binding of RCAN1 to Caln and its extended half-life caused by Dyrk1A-mediated phosphorylation. Furthermore, an increased expression of phospho-Thr(192)-RCAN1 was observed in the brains of transgenic mice overexpressing the Dyrk1A protein. These results suggest a direct link between Dyrk1A and RCAN1 in the Caln-NFAT signaling and Tau hyperphosphorylation pathways, supporting the notion that the synergistic interaction between the chromosome 21 genes RCAN1 and Dyrk1A is associated with a variety of pathological features associated with DS.
Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas Musculares/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Animales , Calcineurina/genética , Calcineurina/metabolismo , Proteínas de Unión al Calcio , Cromosomas Humanos Par 21/genética , Cromosomas Humanos Par 21/metabolismo , Proteínas de Unión al ADN , Síndrome de Down/genética , Síndrome de Down/metabolismo , Glucógeno Sintasa Quinasa 3/genética , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Células HEK293 , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Ratones , Ratones Transgénicos , Proteínas Musculares/genética , Factores de Transcripción NFATC/genética , Factores de Transcripción NFATC/metabolismo , Fosforilación/genética , Unión Proteica/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Tirosina Quinasas/genética , Transducción de Señal/genética , Transcripción Genética/genética , Proteínas tau/genética , Proteínas tau/metabolismo , Quinasas DyrKRESUMEN
Down syndrome (DS) is associated with many neural defects, including reduced brain size and impaired neuronal proliferation, highly contributing to the mental retardation. Those typical characteristics of DS are closely associated with a specific gene group "Down syndrome critical region" (DSCR) on human chromosome 21. Here we investigated the molecular mechanisms underlying impaired neuronal proliferation in DS and, more specifically, a regulatory role for dual-specificity tyrosine-(Y) phosphorylation-regulated kinase 1A (Dyrk1A), a DSCR gene product, in embryonic neuronal cell proliferation. We found that Dyrk1A phosphorylates p53 at Ser-15 in vitro and in immortalized rat embryonic hippocampal progenitor H19-7 cells. In addition, Dyrk1A-induced p53 phosphorylation at Ser-15 led to a robust induction of p53 target genes (e.g. p21(CIP1)) and impaired G(1)/G(0)-S phase transition, resulting in attenuated proliferation of H19-7 cells and human embryonic stem cell-derived neural precursor cells. Moreover, the point mutation of p53-Ser-15 to alanine rescued the inhibitory effect of Dyrk1A on neuronal proliferation. Accordingly, brains from embryonic DYRK1A transgenic mice exhibited elevated levels of Dyrk1A, Ser-15 (mouse Ser-18)-phosphorylated p53, and p21(CIP1) as well as impaired neuronal proliferation. These findings suggest that up-regulation of Dyrk1A contributes to altered neuronal proliferation in DS through specific phosphorylation of p53 at Ser-15 and subsequent p21(CIP1) induction.
Asunto(s)
Ciclo Celular , Síndrome de Down/metabolismo , Embrión de Mamíferos/metabolismo , Neuronas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Animales , Línea Celular , Cromosomas Humanos Par 21/genética , Cromosomas Humanos Par 21/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Síndrome de Down/genética , Síndrome de Down/patología , Embrión de Mamíferos/patología , Humanos , Ratones , Ratones Transgénicos , Neuronas/patología , Fosforilación/genética , Mutación Puntual , Proteínas Serina-Treonina Quinasas/genética , Proteínas Tirosina Quinasas/genética , Ratas , Proteína p53 Supresora de Tumor/genética , Quinasas DyrKRESUMEN
The dual-specificity tyrosine(Y)-phosphorylation-regulated kinase 1A (Dyrk1A) gene is located on human chromosome 21 and encodes a proline-directed protein kinase that might be responsible for mental retardation and early onset of Alzheimer's disease (AD) in Down syndrome (DS) patients. Presenilin 1 (PS1) is a key component of the γ-secretase complex in the generation of ß-amyloid (Aß), an important trigger protein in the pathogenesis of AD. Increased Dyrk1A expression has been reported in human AD and DS brains. We previously showed that Dyrk1A increased Aß production in mammalian cells and transgenic mice that over-express Dyrk1A. In this study, we describe a potential mechanism by which Aß is increased in Dyrk1A-over-expressing DS and AD brains. First, we show that PS1 is phosphorylated by the Dyrk1A at Thr(354) and that this phosphorylation increases γ-secretase activity. Then, using transgenic mice that over-express human Dyrk1A, we demonstrate that phospho-Thr354-PS1 (pT354-PS1) expression is enhanced when Dyrk1A level is increased. We also show that pT354-PS1 is more stable than the unphosphorylated form of PS1. These results reveal a potential regulatory link between Dyrk1A and PS1 in the Aß pathway of DS and AD brains, suggesting that up-regulated Dyrk1A may accelerate AD pathogenesis through PS1 phosphorylation.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Síndrome de Down/metabolismo , Presenilina-1/metabolismo , Proteínas Serina-Treonina Quinasas/fisiología , Proteínas Tirosina Quinasas/fisiología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/biosíntesis , Péptidos beta-Amiloides/genética , Animales , Línea Celular , Semivida , Humanos , Inmunohistoquímica , Inmunoprecipitación , Ratones , Ratones Transgénicos , Fosforilación , Plásmidos/genética , ARN Interferente Pequeño/genética , Quinasas DyrKRESUMEN
Individuals with Down syndrome (DS) suffer from mental retardation. Overexpression and the resulting increased specific activity of Dyrk1A kinase located on chromosome 21 cause a learning and memory deficit in Dyrk1A transgenic mice. To search for therapeutic agents with Dyrk1A inhibition activity, previously we obtained HCD160 as a new hit compound for Dyrk1A inhibition. In the present study, we synthesized 34 HCD160 derivatives to investigate the quantitative structure-activity relationship (QSAR). This analysis could provide important information for novel drug discovery for treatment of DS related learning and memory deficits.