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1.
Int J Mol Sci ; 19(6)2018 May 31.
Artículo en Inglés | MEDLINE | ID: mdl-29857474

RESUMEN

A major cause underlying familial Alzheimer's disease (AD) are mutations in presenilin proteins, presenilin 1 (PS1) and presenilin 2 (PS2). Presenilins are components of the γ-secretase complex which, when mutated, can affect amyloid precursor protein (APP) processing to toxic forms of amyloid beta (Aß). Consequently, presenilins have been the target of numerous and varied research efforts to develop therapeutic strategies for AD. The presenilin 1 gene harbors the largest number of AD-causing mutations resulting in the late onset familial form of AD. As a result, the majority of efforts for drug development focused on PS1 and Aß. Soon after the discovery of the major involvement of PS1 and PS2 in γ-secretase activity, it became clear that neuronal signaling, particularly calcium ion (Ca2+) signaling, is regulated by presenilins and impacted by mutations in presenilin genes. Intracellular Ca2+ signaling not only controls the activity of neurons, but also gene expression patterns, structural functionality of the cytoskeleton, synaptic connectivity and viability. Here, we will briefly review the role of presenilins in γ-secretase activity, then focus on the regulation of Ca2+ signaling, oxidative stress, and cellular viability by presenilins within the context of AD and discuss the relevance of presenilins in AD drug development efforts.


Asunto(s)
Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/metabolismo , Descubrimiento de Drogas , Fenómenos Electrofisiológicos/efectos de los fármacos , Terapia Molecular Dirigida , Presenilinas/antagonistas & inhibidores , Presenilinas/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Autofagia , Calcio/metabolismo , Señalización del Calcio , Humanos , Estrés Oxidativo/efectos de los fármacos , Complejo de la Endopetidasa Proteasomal/metabolismo , Transducción de Señal/efectos de los fármacos
2.
Int J Oncol ; 50(5): 1671-1682, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-28339031

RESUMEN

Long non-coding RNAs (lncRNAs) function in the development and progression of cancer, but only a small portion of lncRNAs have been characterized to date. A novel lncRNA transcript, 2.53 kb in length, was identified by transcriptome sequencing analysis, and was named p53-inducible cancer-associated RNA transcript 1 (PICART1). PICART1 was found to be upregulated by p53 through a p53-binding site at -1808 to -1783 bp. In breast and colorectal cancer cells and tissues, PICART1 expression was found to be decreased. Ectopic expression of PICART1 suppressed the growth, proliferation, migration, and invasion of MCF7, MDA-MB-231 and HCT116 cells whereas silencing of PICART1 stimulated cell growth and migration. In these cells, the expression of PICART1 suppressed levels of p-AKT (Thr308 and Ser473) and p-GSK3ß (Ser9), and accordingly, ß-catenin, cyclin D1 and c-Myc expression were decreased, while p21Waf/cip1 expression was increased. Together these data suggest that PICART1 is a novel p53-inducible tumor-suppressor lncRNA, functioning through the AKT/GSK3ß/ß-catenin signaling cascade.


Asunto(s)
Neoplasias de la Mama/genética , Proliferación Celular/genética , Neoplasias Colorrectales/genética , ARN Largo no Codificante/genética , Proteína p53 Supresora de Tumor/genética , Neoplasias de la Mama/patología , Neoplasias Colorrectales/patología , Ciclina D1/biosíntesis , Femenino , Regulación Neoplásica de la Expresión Génica , Glucógeno Sintasa Quinasa 3 beta/genética , Células HCT116 , Humanos , Células MCF-7 , Proteína Oncogénica v-akt/genética , Proteína p53 Supresora de Tumor/biosíntesis , beta Catenina/genética
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