RESUMEN
Peroxisome proliferator-activated receptor-ß/δ (PPARß/δ) inhibits skin tumorigenesis through mechanisms that may be dependent on HRAS signaling. The present study examined the hypothesis that PPARß/δ promotes HRAS-induced senescence resulting in suppression of tumorigenesis. PPARß/δ expression increased p-ERK and decreased p-AKT activity. Increased p-ERK activity results from the dampened HRAS-induced negative feedback response mediated in part through transcriptional upregulation of RAS guanyl-releasing protein 1 (RASGRP1) by PPARß/δ. Decreased p-AKT activity results from repression of integrin-linked kinase (ILK) and phosphoinositide-dependent protein kinase-1 (PDPK1) expression. Decreased p-AKT activity in turn promotes cellular senescence through upregulation of p53 and p27 expression. Both over-expression of RASGRP1 and shRNA-mediated knockdown of ILK partially restore cellular senescence in Pparß/δ-null cells. Higher PPARß/δ expression is also correlated with increased senescence observed in human benign neurofibromas and colon adenoma lesions in vivo. These results demonstrate that PPARß/δ promotes senescence to inhibit tumorigenesis and provide new mechanistic insights into HRAS-induced cellular senescence.
Asunto(s)
Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , PPAR delta/metabolismo , PPAR-beta/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas ras/metabolismo , Envejecimiento/genética , Envejecimiento/metabolismo , Animales , Western Blotting , Carcinogénesis/genética , Carcinogénesis/metabolismo , Células Cultivadas , Senescencia Celular/genética , Femenino , Células HEK293 , Humanos , Queratinocitos/citología , Queratinocitos/metabolismo , Ratones , Ratones Noqueados , Células 3T3 NIH , PPAR delta/genética , PPAR-beta/genética , Fosforilación , Interferencia de ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Proteínas ras/genéticaRESUMEN
Dental porcelain frits have been prepared by the gel route, a procedure involving solubilization of alkalies, boron, rare earth, and other compounds in an alumina-silica sol. Using this procedure, porcelain frits suitable for metal-ceramic application have been prepared that fire to maturity at temperatures lower than current commercial porcelains. Solubilities, translucencies, thermal expansion coefficients, dilatometric softening temperatures, and flexure strengths are within the ranges of current commercial porcelains. The high degree of dispersion of pigments and phosphors made possible by gel route technology and the technology's ability to disperse crystalline phases to strengthen porcelain offers many processing advantages. Gel route technology also offers a great degree of freedom in modifying porcelain properties.
