RESUMEN
Mammalian pancreatic β-cells play a pivotal role in development and glucose homeostasis through the production and secretion of insulin. Functional failure or decrease in β-cell number leads to type 2 diabetes (T2D). Despite the physiological importance of β-cells, the viability of β-cells is often challenged mainly due to its poor ability to adapt to their changing microenvironment. One of the factors that negatively affect β-cell viability is high concentration of free fatty acids (FFAs) such as palmitate. In this work, we demonstrated that Yes-associated protein (Yap1) is activated when β-cells are treated with palmitate. Our loss- and gain-of-function analyses using rodent insulinoma cell lines revealed that Yap1 suppresses palmitate-induced apoptosis in β-cells without regulating their proliferation. We also found that upon palmitate treatment, re-arrangement of F-actin mediates Yap1 activation. Palmitate treatment increases expression of one of the Yap1 target genes, connective tissue growth factor (CTGF). Our gain-of-function analysis with CTGF suggests CTGF may be the downstream factor of Yap1 in the protective mechanism against FFA-induced apoptosis.
Asunto(s)
Animales , Humanos , Ratones , Ratas , Actinas , Metabolismo , Proteínas Adaptadoras Transductoras de Señales , Genética , Metabolismo , Apoptosis , Fisiología , Compuestos Bicíclicos Heterocíclicos con Puentes , Farmacología , Línea Celular Tumoral , Factor de Crecimiento del Tejido Conjuntivo , Genética , Metabolismo , Farmacología , Citocalasina D , Farmacología , Ácidos Grasos no Esterificados , Farmacología , Células HEK293 , Inmunohistoquímica , Células Secretoras de Insulina , Biología Celular , Metabolismo , Microscopía Fluorescente , Ácido Palmítico , Farmacología , Fosfoproteínas , Genética , Metabolismo , Interferencia de ARN , ARN Interferente Pequeño , Metabolismo , Proteínas Recombinantes , Genética , Metabolismo , Farmacología , Tiazolidinas , FarmacologíaRESUMEN
Hippo signaling plays a crucial role in growth control and tumor suppression by regulating cell proliferation, apoptosis, and differentiation. How Hippo signaling is regulated has been under extensive investigation. Over the past three years, an increasing amount of data have supported a model of actin cytoskeleton blocking Hippo signaling activity to allow nuclear accumulation of a downstream effector, Yki/Yap/Taz. On the other hand, Hippo signaling negatively regulates actin cytoskeleton organization. This review provides insight on the mutual regulatory mechanisms between Hippo signaling and actin cytoskeleton for a tight control of cell behaviors during animal development, and points out outstanding questions for further investigations.