RESUMEN
BACKGROUND AND PURPOSE: Growth of subependymal giant cell tumor and subependymal nodules has not been well-characterized. The purpose of this study was to determine whether growth curves can differentiate subependymal giant cell tumors from subependymal nodules. MATERIALS AND METHODS: Brain MR imaging of patients with tuberous sclerosis complex were retrospectively reviewed from 2002 to 2018. All lesions in the region of the foramen of Monro were measured. Lesions were categorized on the basis of maximal diameter at the most recent scan: small lesions (<1 cm), indeterminate lesions (>1 cm), and resected lesions (>1 cm and surgically resected). Growth velocity and acceleration on serial imaging were analyzed, and growth rates were calculated between 0 and 20 years of age and compared among the 3 categories. RESULTS: Forty-one patients were analyzed. The average age at the earliest scan was 5.9 (SD = 5.7) years. One hundred twenty-six small, 27 indeterminate, and 10 resected lesions were measured. Subependymal giant cell tumors grew faster than indeterminate lesions between 6 and 15 years of age. Indeterminate lesions grew faster than small lesions at 0-10 years of age. Resected lesions showed increased velocity and acceleration of growth compared with indeterminate lesions and small lesions on serial imaging. CONCLUSIONS: Growth differentiates subependymal nodules and subependymal giant cell tumors within the first 20 years of life, and the use of velocity and acceleration of growth may refine the diagnostic criteria of subependymal giant cell tumors. Additionally, 6-15 years of age may be an important period to monitor subependymal giant cell tumors at the foramen of Monro because increased growth may help to identify subependymal giant cell tumors that will continue to grow and result in obstructive hydrocephalus.
Asunto(s)
Astrocitoma , Neoplasias Encefálicas , Tumores de Células Gigantes , Esclerosis Tuberosa , Astrocitoma/diagnóstico por imagen , Neoplasias Encefálicas/diagnóstico por imagen , Humanos , Estudios Retrospectivos , Esclerosis Tuberosa/complicaciones , Esclerosis Tuberosa/diagnóstico por imagenRESUMEN
BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder characterized by benign hamartomas occurring in multiple organ systems including the brain, kidneys, heart, lungs, liver, skin, and the eyes. Typical retinal findings associated with TSC include astrocytic hamartoma and achromic patch. While rare cases of cataract occurring in the setting of TSC have been reported, this is the first analysis of a large series of individuals with TSC that aims to quantify the frequency of this finding and to describe its clinical and genetic associations. MATERIALS AND METHODS: This is a retrospective chart review of 244 patients from the Herscot Center for Tuberous Sclerosis Complex at the Massachusetts General Hospital who underwent complete ophthalmic examination. We describe the clinical and genetic findings in five individuals with TSC and juvenile cataract. RESULTS: Four of five cases (80%) were unilateral. The cataract was described as having an anterior subcapsular component in 3 of 5 cases (60%). Three individuals (60%) underwent lensectomy with intraocular lens (IOL) implant and two individuals (40%) were observed. Genetic testing revealed a known disease-causing mutation in TSC2 in 100% of cases. CONCLUSIONS: Recent evidence suggests that mTOR signaling may play a role in cataract formation which could explain the relatively high incidence of juvenile cataract in this population. Juvenile cataract is a potentially under-recognized ocular manifestation of TSC.
Asunto(s)
Catarata/patología , Mutación , Proteína 2 del Complejo de la Esclerosis Tuberosa/genética , Esclerosis Tuberosa/patología , Adulto , Catarata/complicaciones , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Pronóstico , Estudios Retrospectivos , Esclerosis Tuberosa/complicacionesRESUMEN
Tuberous sclerosis complex (TSC) is caused by a mutation in the TSC1 or TSC2 genes. However, 15% of patients have no mutation identified. Tubers and subependymal nodules (SENs) are the typical brain lesions in TSC and are present in 90-95% of patients. The objective of this study is to characterize the specific genotype-phenotype of patients without these lesions. We analyzed the features of 11 patients without typical TSC neuroanatomic features. Ten had TSC1/TSC2 mutational analysis, which was negative. Clinically they had lesions thought to be of neural crest (NC) origin, such as hypomelanotic macules, facial angiofibromas, cardiac rhabdomyomas, angiomyolipomas, and lymphangioleiomyomatosis. We hypothesize that patients without tubers and SENs reflect mosaicism caused by a mutation in TSC1 or TSC2 in a NC cell during embryonic development. This may explain the negative results in TSC1 and TSC2 testing in DNA from peripheral leukocytes.
Asunto(s)
Encéfalo/patología , Esclerosis Tuberosa/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Estudios de Asociación Genética , Humanos , Lactante , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Hepatic manifestations of tuberous sclerosis complex: a genotypic and phenotypic analysis. A retrospective review of the clinical records and radiological images of 205 patients with tuberous sclerosis complex (TSC) was performed to evaluate the prevalence and progression of hepatic lesions; examine the association of hepatic phenotype with genotype, age, and gender; and investigate the relationships between hepatic, renal, and pulmonary involvement. Hepatic angiomyolipomas (AML), cysts, and other benign lesions were identified in 30% of the cohort, and some lesions grew significantly over time. However, no patient had clinical symptoms or complications from hepatic lesions. TSC2 patients exhibited a higher frequency of AML compared to TSC1 patients (p = 0.037), and patients with no mutation identified exhibited a higher frequency of cysts compared to TSC2 patients (p = 0.023). Age was positively correlated with frequency of hepatic involvement (p < 0.001), whereas hepatic phenotype was independent of gender. Presence of hepatic AML was associated with presence of renal AML (p = 0.001). These findings confirm a high rate of asymptomatic hepatic lesions in TSC and further characterize the TSC phenotype.
Asunto(s)
Angiomiolipoma/diagnóstico por imagen , Angiomiolipoma/epidemiología , Fenotipo , Esclerosis Tuberosa/epidemiología , Esclerosis Tuberosa/genética , Proteínas Supresoras de Tumor/genética , Adolescente , Adulto , Factores de Edad , Niño , Femenino , Genotipo , Humanos , Hígado/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Mutación/genética , Prevalencia , Análisis de Regresión , Factores Sexuales , Tomografía Computarizada por Rayos X , Esclerosis Tuberosa/diagnóstico por imagen , Proteína 1 del Complejo de la Esclerosis Tuberosa , Proteína 2 del Complejo de la Esclerosis TuberosaRESUMEN
We explored pancreatic neuroendocrine tumors (PanNETs) associated with tuberous sclerosis complex (TSC) to determine their incidence in the TSC population; define their clinical, radiological, and pathological characteristics; and investigate their association with underlying genotypes. Retrospectively reviewed abdominal imaging of 219 patients with TSC, evaluating the incidence, size, and architecture of pancreatic lesions. Pathology records at Massachusetts General Hospital (MGH) were reviewed for all PanNET diagnoses in patients with TSC. Literature was reviewed for TSC-related PanNET cases. Nine patients with TSC were found to have a pancreatic lesion(s) on abdominal imaging and six patients have been diagnosed with a PanNET by pathology at MGH. Twelve cases of TSC-associated PanNETs have been reported in the literature. Of these 18 PanNET cases, one third were cystic, and the average age at resection was 26 years. Germline TSC2 mutations were found in all patients for whom genetic data were available (n = 3). We did not identify pancreatic angiomyolipomas in this series. Our results suggest that PanNETs are the most common pancreatic lesion in patients with TSC. Focal pancreatic mass lesions, solid or cystic, in patients with TSC should be considered possible PanNETs, and resection of the lesion may be clinically indicated.
Asunto(s)
Tumores Neuroendocrinos/diagnóstico por imagen , Tumores Neuroendocrinos/epidemiología , Neoplasias Pancreáticas/diagnóstico por imagen , Neoplasias Pancreáticas/epidemiología , Esclerosis Tuberosa/diagnóstico por imagen , Esclerosis Tuberosa/epidemiología , Proteínas Supresoras de Tumor/genética , Adulto , Niño , Femenino , Mutación de Línea Germinal/genética , Humanos , Incidencia , Masculino , Massachusetts/epidemiología , Persona de Mediana Edad , Tumores Neuroendocrinos/genética , Neoplasias Pancreáticas/genética , Tomografía Computarizada por Rayos X , Esclerosis Tuberosa/genética , Proteína 2 del Complejo de la Esclerosis TuberosaAsunto(s)
Huesos/patología , Encéfalo/patología , Esclerosis Tuberosa/patología , Huesos/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Calcinosis/diagnóstico por imagen , Calcinosis/patología , Femenino , Humanos , Metaplasia/diagnóstico por imagen , Metaplasia/patología , Radiografía , Esclerosis Tuberosa/diagnóstico por imagen , Adulto JovenRESUMEN
OBJECTIVE: The purpose of this study was to assess the prevalence of and to identify epidemiologic, genetic, electrophysiologic, and neuroanatomic risk factors for autism spectrum disorders (ASD) in a cohort of patients with tuberous sclerosis complex (TSC). METHODS: A total of 103 patients with TSC were evaluated for ASD. A retrospective review of patients' records was performed, including mutational analysis. EEG reports were analyzed for the presence of ictal and interictal epileptiform features. Brain MRI scans were evaluated for TSC neuropathology, including tuber burden. RESULTS: Of the 103 patients with TSC, 40%were diagnosed with an ASD. On univariate analysis, patients with ASD were less likely to have mutations in the TSC1 gene. Patients with ASD also had an earlier age at seizure onset and more frequent seizures. On EEG, those with ASD had a significantly greater amount of interictal epileptiform features in the left temporal lobe only. On MRI, there were no differences in the regional distribution of tuber burden, although those with TSC2 and ASD had a higher prevalence of cyst-like tubers. CONCLUSIONS: The development of ASD in TSC is not well understood. Given our findings, ASD may be associated with persistent seizure activity early in development in particular brain regions, such as those responsible for social perception and communication in the left temporal lobe. The presence of cyst-like tubers on MRI could provide a structural basis or marker for ASD pathology in TSC, although studies assessing their effect on cortical function are needed.
Asunto(s)
Trastornos Generalizados del Desarrollo Infantil/etiología , Esclerosis Tuberosa/complicaciones , Adolescente , Adulto , Edad de Inicio , Encéfalo/patología , Encéfalo/fisiopatología , Niño , Trastornos Generalizados del Desarrollo Infantil/genética , Trastornos Generalizados del Desarrollo Infantil/patología , Trastornos Generalizados del Desarrollo Infantil/fisiopatología , Preescolar , Electroencefalografía , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Esclerosis Tuberosa/genética , Esclerosis Tuberosa/patología , Esclerosis Tuberosa/fisiopatología , Proteína 2 del Complejo de la Esclerosis Tuberosa , Proteínas Supresoras de Tumor/genéticaRESUMEN
BACKGROUND: Lymphangioleiomyomatosis (LAM) is a prominent finding in the setting of tuberous sclerosis complex (TSC). OBJECTIVE: The present study was designed to compare cystic lung changes consistent with LAM in patients with a TSC1 disease-causing mutation, TSC2 disease-causing mutation, or no mutation identified (NMI). METHODS AND RESULTS: We conducted a retrospective review of the chest computed tomography (CT) of 45 female and 20 male patients with TSC and found cysts consistent with LAM in 22 (49%) women and two (10%) men. In the female population, changes consistent with LAM were observed in six of 15 (40%) patients with TSC1, 11 of 23 (48%) with TSC2, and five of seven (71%) with NMI. While the predominant size of cysts did not differ across these three groups, TSC2 women with LAM had a significantly greater number of cysts than did TSC1 patients (p = 0.010). CONCLUSIONS: These findings suggest a higher rate of LAM in TSC1 than previously recognised, as well as a fundamental difference in CT presentation between TSC1 and TSC2.
Asunto(s)
Linfangioleiomiomatosis/genética , Mutación , Esclerosis Tuberosa/genética , Proteínas Supresoras de Tumor/genética , Adulto , Distribución de Chi-Cuadrado , Estudios de Cohortes , Análisis Mutacional de ADN , Femenino , Humanos , Linfangioleiomiomatosis/diagnóstico por imagen , Masculino , Radiografía Torácica , Estudios Retrospectivos , Estadísticas no Paramétricas , Esclerosis Tuberosa/diagnóstico por imagen , Proteína 1 del Complejo de la Esclerosis Tuberosa , Proteína 2 del Complejo de la Esclerosis TuberosaRESUMEN
We describe three cases in whom identification of a disease-causing mutation in the TSC1 or TSC2 gene preceded the appearance or detection of symptoms sufficient for a clinical diagnosis of tuberous sclerosis complex (TSC). We suggest that genetic testing be given a more prominent role in the evaluation of individuals with a family history of TSC or symptoms suggestive of TSC and propose that diagnostic criteria be revised to include genetic testing.
Asunto(s)
Análisis Mutacional de ADN , Esclerosis Tuberosa/diagnóstico , Anciano , Niño , Preescolar , Femenino , Humanos , Masculino , Estudios Retrospectivos , Esclerosis Tuberosa/patología , Proteína 1 del Complejo de la Esclerosis Tuberosa , Proteína 2 del Complejo de la Esclerosis Tuberosa , Proteínas Supresoras de Tumor/genéticaRESUMEN
Tuberous Sclerosis Complex (TSC) is a multi-system disorder that is highly variable in its clinical presentation. Current molecular diagnostic methods permit identification of mutations in either TSC1 or TSC2 in 75-85% of TSC patients. Here we examine the clinical characteristics of those TSC patients who have no mutation identified (NMI). A retrospective review of our patient population that had comprehensive testing for mutations in TSC1/TSC2 identified 23/157 (15%) that were NMI. NMI patients had a lower incidence of brain findings on imaging studies, neurological features, and renal findings than those with TSC2 mutations. In contrast, NMI patients had a lower incidence of seizures than TSC patients with TSC1 mutations, but had a higher incidence of both renal angiomyolipomas and pulmonary lymphangioleiomyomatosis. This distinct constellation of findings suggest that NMI patients may have a unique molecular pathogenesis, different from that seen in TSC patients with the usual mutations in TSC1 and TSC2. We suggest that the mechanisms of disease in these patients include both mosaicism for a TSC2 mutation, and unusual non-coding region mutations in TSC2.
Asunto(s)
Esclerosis Tuberosa/genética , Esclerosis Tuberosa/fisiopatología , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Esclerosis Tuberosa/diagnóstico , Esclerosis Tuberosa/patología , Proteína 1 del Complejo de la Esclerosis Tuberosa , Proteína 2 del Complejo de la Esclerosis Tuberosa , Proteínas Supresoras de Tumor/genética , Adulto JovenRESUMEN
The digenean trematode Schistosoma mansoni is responsible for chronic schistosomiasis worldwide, and in Brazil alone an estimated 35 million people are at risk. To evaluate epidemiological patterns among human definitive hosts, we assessed genetic diversity and population subdivision of S. mansoni infrapopulations in human hosts from the highly endemic village of Virgem das Graças in the state of Minas Gerais, Brazil. We believe this is the largest such survey to date. Genetic diversity of parasites, measured over eight polymorphic microsatellite loci, was relatively high and standard measures of inbreeding indicated that the population was panmictic. Furthermore, there was no significant isolation-by-distance of parasite infrapopulations, and measures of population subdivision indicated significant but low to moderate levels of population differentiation. We conclude that patients within this village sample from a broad range of schistosome genetic diversity and effectively act as "genetic mixing bowls" for the parasites. These results contrast with those previously observed in the Brazilian village of Melqui ades and thus provide the opportunity for comparisons of environmental and epidemiological differences that are likely to influence host-parasite coevolution and parasite transmission.
Asunto(s)
ADN de Helmintos/análisis , Variación Genética , Interacciones Huésped-Parásitos , Polimorfismo Genético , Schistosoma mansoni/genética , Animales , Biomphalaria/parasitología , Brasil , Humanos , Estadios del Ciclo de Vida , Ratones , Ratones Endogámicos BALB C , Recuento de Huevos de Parásitos , Técnica del ADN Polimorfo Amplificado Aleatorio , Esquistosomiasis mansoni/parasitología , Esquistosomiasis mansoni/transmisiónAsunto(s)
Neoplasias Cardíacas/complicaciones , Lipoma/complicaciones , Esclerosis Tuberosa/complicaciones , Adulto , Angiomiolipoma/complicaciones , Angiomiolipoma/genética , Femenino , Neoplasias Cardíacas/diagnóstico por imagen , Neoplasias Cardíacas/genética , Humanos , Neoplasias Renales/complicaciones , Neoplasias Renales/genética , Lipoma/diagnóstico por imagen , Lipoma/genética , Masculino , Persona de Mediana Edad , Neoplasias Primarias Múltiples/complicaciones , Neoplasias Primarias Múltiples/genética , Radiografía , Esclerosis Tuberosa/genéticaRESUMEN
Tuberous sclerosis complex is a genetic disorder characterized by hamartomatous lesions in multiple organs, frequently involving the kidney. We conducted a retrospective review of the clinical and radiographic records of 167 patients with tuberous sclerosis to determine the frequency of renal disease, the likelihood of significant renal morbidity, and the effects of genotype (TSC1 vs TSC2) and gender on renal phenotype. Renal lesions were seen in 57.5% of patients. Of these, angiomyolipoma (AML) occurred in 85.4%, cysts in 44.8%, and renal cell carcinoma in 4.2%. Both AML and cysts were significantly more common and more numerous in TSC2 than in TSC1. AML was significantly more common in female than in male patients, but cysts showed no correlation with gender. Eleven patients developed renal abnormalities during their care in this practice at an average age of onset of 11.3 years (range 3.8-23 years). The frequency and number of renal lesions were positively correlated with age. Interventions, including arterial embolization and nephrectomy, were performed in 11 (6.6%) patients. Among female patients with lymphangioleiomyomatosis, renal AML was universally present. Our findings confirm a high rate of renal involvement; a low rate of serious complications; significant associations between renal involvement, genotype, and gender; and a significant association between renal and pulmonary involvement in female patients.
Asunto(s)
Angiomiolipoma/etiología , Carcinoma de Células Renales/etiología , Neoplasias Renales/etiología , Linfangioleiomiomatosis/etiología , Esclerosis Tuberosa/complicaciones , Adolescente , Adulto , Factores de Edad , Angiomiolipoma/epidemiología , Angiomiolipoma/patología , Carcinoma de Células Renales/epidemiología , Carcinoma de Células Renales/patología , Niño , Preescolar , Femenino , Genotipo , Humanos , Incidencia , Lactante , Recién Nacido , Neoplasias Renales/epidemiología , Neoplasias Renales/patología , Linfangioleiomiomatosis/epidemiología , Linfangioleiomiomatosis/patología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Estudios Retrospectivos , Factores Sexuales , Esclerosis Tuberosa/epidemiología , Esclerosis Tuberosa/genética , Esclerosis Tuberosa/patologíaRESUMEN
OBJECTIVE: To evaluate the sensitivity of a simultaneous whole-head 306-channel magnetoencephalography (MEG)/70-electrode EEG recording to detect interictal epileptiform activity (IED) in a prospective, consecutive cohort of patients with medically refractory epilepsy that were considered candidates for epilepsy surgery. METHODS: Seventy patients were prospectively evaluated by simultaneously recorded MEG/EEG. All patients were surgical candidates or were considered for invasive EEG monitoring and had undergone an extensive presurgical evaluation at a tertiary epilepsy center. MEG and EEG raw traces were analysed individually by two independent reviewers. RESULTS: MEG data could not be evaluated due to excessive magnetic artefacts in three patients (4%). In the remaining 67 patients, the overall sensitivity to detect IED was 72% (48/67 patients) for MEG and 61% for EEG (41/67 patients) analysing the raw data. In 13% (9/67 patients), MEG-only IED were recorded, whereas in 3% (2/67 patients) EEG-only IED were recorded. The combined sensitivity was 75% (50/67 patients). CONCLUSION: Three hundred and six-channel MEG has a similarly high sensitivity to record IED as EEG and appears to be complementary. In one-third of the EEG-negative patients, MEG can be expected to record IED, especially in the case of lateral neocortical epilepsy and/or cortical dysplasia.
Asunto(s)
Electroencefalografía , Epilepsias Parciales/patología , Magnetoencefalografía , Cuidados Preoperatorios , Adolescente , Adulto , Niño , Epilepsias Parciales/fisiopatología , Epilepsias Parciales/cirugía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Sensibilidad y EspecificidadRESUMEN
Epilepsy is common in the pediatric population and can significantly affect the health and quality of life of the child and family. There are many causes of childhood seizures and many forms of treatment, including pharmacologic and surgical modalities. Psychiatric disease occurs with higher incidence in children with epilepsy, and psychiatric disease in children also must be differentiated from epilepsy. Many medications are used to treat epilepsy and psychiatric disease, all of which interact with each other pharmacodynamically, as well as acting on the clinical manifestations of the disorders. These factors, and the complicated interface between epilepsy and psychiatry, must be considered in the successful management of children with epilepsy.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Terapias Complementarias/métodos , Epilepsia , Trastornos Mentales/complicaciones , Adolescente , Anticonvulsivantes/efectos adversos , Niño , Diagnóstico Diferencial , Epilepsia/complicaciones , Epilepsia/diagnóstico , Epilepsia/tratamiento farmacológico , Epilepsia/terapia , Humanos , Trastornos Mentales/diagnóstico , Trastornos Mentales/tratamiento farmacológico , Procedimientos Neuroquirúrgicos , Psicotrópicos/efectos adversos , Psicotrópicos/uso terapéuticoRESUMEN
Partial seizures and asymmetric abnormalities seen on electroencephalogram (EEG) are infrequent in juvenile myoclonic epilepsy, but when present, can lead to a misdiagnosis of partial seizures. We report four patients with juvenile myoclonic epilepsy who had generalized spike or polyspike and wave discharges on EEG in addition to clinical and EEG evidence of focality. The clinical course and response to therapy was similar to that in typical juvenile myoclonic epilepsy.
Asunto(s)
Electroencefalografía , Epilepsias Mioclónicas/diagnóstico , Epilepsias Parciales/diagnóstico , Adolescente , Adulto , Edad de Inicio , Anticonvulsivantes/uso terapéutico , Carbamazepina/uso terapéutico , Diagnóstico Diferencial , Epilepsias Mioclónicas/tratamiento farmacológico , Epilepsias Parciales/tratamiento farmacológico , Femenino , Humanos , Masculino , Triazinas/uso terapéutico , Ácido Valproico/uso terapéuticoRESUMEN
Acute disseminated encephalomyelitis (ADEM), a postinfectious illness of the central nervous system (CNS), is thought to be an autoimmune disease. Here, we characterized the cytokines secreted by myelin-reactive T cells generated from patients with ADEM. The frequency of MBP-reactive T cell lines was ten-fold higher in patients with ADEM compared to patients with encephalitis and normal subjects. Whereas there was no significant IFN-gamma secretion, the predominant cytokine secreted by MBP-reactive T cell lines was IL-4 in patients with ADEM. In contrast, IL-4 secretion was only rarely detected in the controls. The presence of high frequencies of MBP-reactive IL-4 secreting T cells in subjects with ADEM during their recovery phase may be similar to myelin reactive IL-4 secreting T cells observed during the spontaneous recovery of animals with EAE.
Asunto(s)
Encefalomielitis Aguda Diseminada/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Proteína Básica de Mielina/análisis , Proteína Básica de Mielina/inmunología , Linfocitos T/química , Anticuerpos Antivirales , Autoinmunidad/inmunología , Niño , Preescolar , Enfermedades Desmielinizantes/inmunología , Enfermedades Desmielinizantes/metabolismo , Enfermedades Desmielinizantes/virología , Encefalomielitis Aguda Diseminada/metabolismo , Encefalomielitis Autoinmune Experimental/metabolismo , Epítopos , Femenino , Herpes Zóster/inmunología , Herpesvirus Humano 3/inmunología , Humanos , Lactante , Interferón gamma/inmunología , Interleucina-2/inmunología , Interleucina-4/inmunología , Masculino , Linfocitos T/inmunología , Linfocitos T/virologíaRESUMEN
The mechanisms by which growth factor-induced signals are propagated to the nucleus, leading to the activation of the transcription factor CREB, have been characterized. Nerve growth factor (NGF) was found to activate multiple signaling pathways that mediate the phosphorylation of CREB at the critical regulatory site, serine 133 (Ser-133). NGF activates the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinases (MAPKs), which in turn activate the pp90 ribosomal S6 kinase (RSK) family of Ser/Thr kinases, all three members of which were found to catalyze CREB Ser-133 phosphorylation in vitro and in vivo. In addition to the ERK/RSK pathway, we found that NGF activated the p38 MAPK and its downstream effector, MAPK-activated protein kinase 2 (MAPKAP kinase 2), resulting in phosphorylation of CREB at Ser-133. Inhibition of either the ERK/RSK or the p38/MAPKAP kinase 2 pathway only partially blocked NGF-induced CREB Ser-133 phosphorylation, suggesting that either pathway alone is sufficient for coupling the NGF signal to CREB activation. However, inhibition of both the ERK/RSK and the p38/MAPKAP kinase 2 pathways completely abolished NGF-induced CREB Ser-133 phosphorylation. These findings indicate that NGF activates two distinct MAPK pathways, both of which contribute to the phosphorylation of the transcription factor CREB and the activation of immediate-early genes.