RESUMEN
Deficits in the Notch pathway are involved in a number of neurologic diseases associated with mental retardation or/and dementia. The mechanisms by which Notch dysregulation are associated with mental retardation and dementia are poorly understood. We found that Notch1 is highly expressed in the adult-born immature neurons in the hippocampus of mice. Retrovirus mediated knockout of notch1 in single adult-born immature neurons decreases mTOR signaling and compromises their dendrite morphogenesis. In contrast, overexpression of Notch1 intracellular domain (NICD), to constitutively activate Notch signaling in single adult-born immature neurons, promotes mTOR signaling and increases their dendrite arborization. Using a unique genetic approach to conditionally and selectively knockout notch 1 in the postnatally born immature neurons in the hippocampus decreases mTOR signaling, compromises their dendrite morphogenesis, and impairs spatial learning and memory. Conditional overexpression of NICD in the postnatally born immature neurons in the hippocampus increases mTOR signaling and promotes dendrite arborization. These data indicate that Notch signaling plays a critical role in dendrite development of immature neurons in the postnatal brain, and dysregulation of Notch signaling in the postnatally born neurons disrupts their development and thus contributes to the cognitive deficits associated with neurological diseases.
Asunto(s)
Envejecimiento/metabolismo , Dendritas/metabolismo , Hipocampo/patología , Trastornos de la Memoria/patología , Neurogénesis , Receptor Notch1/metabolismo , Transducción de Señal , Animales , Animales Recién Nacidos , Giro Dentado/metabolismo , Integrasas/metabolismo , Trastornos de la Memoria/metabolismo , Ratones Noqueados , Plasticidad Neuronal , Dominios Proteicos , Receptor Notch1/química , Retroviridae/metabolismo , Proteína S6 Ribosómica/metabolismo , Memoria Espacial , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
BACKGROUND: Cigarette smoking has been verified as the risk factor of esophageal squamous cell carcinoma (ESCC). Overexpression of cyclooxygenase 2 (COX-2) is shown in ESCC. The objective of this study was to investigate the effects of cigarette smoking ethanol extract (EE) on the proliferation of the human ESCC cell lines, and to explore the correlation between the proliferation rate of human ESCC cell lines and the expression pattern of COX-2. Whether aspirin can inhibit the proliferation of the ESCC cell lines pretreated with EE, and regulate the mRNA expression levels of COX-2 are also examined. METHODS: Two human ESCC cell lines were selected. EC109 was poorly differentiated and EC9706 was highly differentiated. EC109 and EC9706 were treated with EE and aspirin for different time course. The cell growth of ESCC was measured by MTT reduction assay and the expression of COX-2 was measured by RT-PCR and Western blot analysis. RESULTS: EE promoted the proliferation of EC109 and EC9706 in dose- and time-dependent manners. In the concentration range (10 - 100 microg/ml for EE) and in the time range (24 - 72 hours) after addition of EE, the cell proliferation was prominent in an up-scaled manner respectively. Aspirin could inhibit the proliferation of cell lines EC109 and EC9706, pretreated with EE for 5 hours, in a dose-dependent manner. In the concentration range (0.5 - 8.0 mmol/L for aspirin), the cell growth inhibition was prominent in an up-scaled manner accordingly (P < 0.05). The effect of EE on cell proliferation was correlated with the up-regulation of COX-2 gene. However, the cell growth inhibition of aspirin was correlated with the down-regulation of COX-2 gene. CONCLUSIONS: EE can stimulate the proliferation of human ESCC cell lines EC109 and EC9706, most likely through up-regulating the expression of COX-2. Aspirin can inhibit the proliferation of ESCC cell lines induced by EE, which suggests it may be advantageous in the chemoprevention and therapy of human tobacco-related ESCC. And its effect is likely to be related with modulating COX-2 activity.