RESUMO
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.
Assuntos
Animais , Humanos , Camundongos , Ratos , Actinas , Metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Genética , Metabolismo , Apoptose , Fisiologia , Compostos Bicíclicos Heterocíclicos com Pontes , Farmacologia , Linhagem Celular Tumoral , Fator de Crescimento do Tecido Conjuntivo , Genética , Metabolismo , Farmacologia , Citocalasina D , Farmacologia , Ácidos Graxos não Esterificados , Farmacologia , Células HEK293 , Imuno-Histoquímica , Células Secretoras de Insulina , Biologia Celular , Metabolismo , Microscopia de Fluorescência , Ácido Palmítico , Farmacologia , Fosfoproteínas , Genética , Metabolismo , Interferência de RNA , RNA Interferente Pequeno , Metabolismo , Proteínas Recombinantes , Genética , Metabolismo , Farmacologia , Tiazolidinas , FarmacologiaRESUMO
In recent years, human cancer genome projects provide unprecedented opportunities for the discovery of cancer genes and signaling pathways that contribute to tumor development. While numerous gene mutations can be identified from each cancer genome, what these mutations mean for cancer is a challenging question to address, especially for those from less understood putative new cancer genes. As a powerful approach, in silico bioinformatics analysis could efficiently sort out mutations that are predicted to damage gene function. Such an analysis of human large tumor suppressor genes, LATS1 and LATS2, has been carried out and the results support a role of hLATS1//2 as negative growth regulators and tumor suppressors.
Assuntos
Animais , Humanos , Camundongos , Proteínas Adaptadoras de Transdução de Sinal , Química , Metabolismo , Proteínas de Transporte , Química , Metabolismo , Biologia Computacional , Genes Neoplásicos , Proteínas com Domínio LIM , Química , Metabolismo , Mutação , Neoplasias , Genética , Patologia , Fosfoproteínas , Química , Metabolismo , Fosforilação , Ligação Proteica , Estrutura Terciária de Proteína , Proteínas Serina-Treonina Quinases , Química , Genética , Metabolismo , Transferases (Outros Grupos de Fosfato Substituídos) , Química , Metabolismo , Proteínas Supressoras de Tumor , Química , Genética , MetabolismoRESUMO
The loss of or decreased functional pancreatic β-cell is a major cause of type 1 and type 2 diabetes. Previous studies have shown that adult β-cells can maintain their ability for a low level of turnover through replication and neogenesis. Thus, a strategy to prevent and treat diabetes would be to enhance the ability of β-cells to increase the mass of functional β-cells. Consequently, much effort has been devoted to identify factors that can effectively induce β-cell expansion. This review focuses on recent reports on small molecules and protein factors that have been shown to promote β-cell expansion.
Assuntos
Humanos , Comunicação Celular , Genética , Diferenciação Celular , Genética , Proliferação de Células , Diabetes Mellitus Tipo 1 , Genética , Patologia , Diabetes Mellitus Tipo 2 , Genética , Patologia , Células Secretoras de Insulina , Química , Metabolismo , PatologiaRESUMO
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.