Inhibition of Mitogen-Activated Protein Kinase Erk1/2 Promotes Protein Degradation of ATP Binding Cassette Transporters A1 and G1 in CHO and in HuH7 cells.

Signal transduction modulates expression and activity of cholesterol transporters. We recently demonstrated that the Ras/mitogen-activated protein kinase (MAPK) signaling cascade regulates protein stability of Scavenger Receptor BI (SR-BI) through Proliferator Activator Receptor (PPARα) -dependent degradation pathways. In addition, MAPK (Mek/Erk 1/2) inhibition has been shown to influence liver X receptor (LXR) -inducible ATP Binding Cassette (ABC) transporter ABCA1 expression in macrophages. Here we investigated if Ras/MAPK signaling could alter expression and activity of ABCA1 and ABCG1 in steroidogenic and hepatic cell lines. We demonstrate that in Chinese Hamster Ovary (CHO) cells and human hepatic HuH7 cells, extracellular signal-regulated kinase 1/2 (Erk1/2) inhibition reduces PPARα-inducible ABCA1 protein levels, while ectopic expression of constitutively active H-Ras, K-Ras and MAPK/Erk kinase 1 (Mek1) increases ABCA1 protein expression, respectively. Furthermore, Mek1/2 inhibitors reduce ABCG1 protein levels in ABCG1 overexpressing CHO cells (CHO-ABCG1) and human embryonic kidney 293 (HEK293) cells treated with LXR agonist. This correlates with Mek1/2 inhibition reducing ABCG1 cell surface expression and decreasing cholesterol efflux onto High Density Lipoproteins (HDL). Real Time reverse transcriptase polymerase chain reaction (RT-PCR) and protein turnover studies reveal that Mek1/2 inhibitors do not target transcriptional regulation of ABCA1 and ABCG1, but promote ABCA1 and ABCG1 protein degradation in HuH7 and CHO cells, respectively. In line with published data from mouse macrophages, blocking Mek1/2 activity upregulates ABCA1 and ABCG1 protein levels in human THP1 macrophages, indicating opposite roles for the Ras/MAPK pathway in the regulation of ABC transporter activity in macrophages compared to steroidogenic and hepatic cell types. In summary, this study suggests that Ras/MAPK signaling modulates PPARα- and LXR-dependent protein degradation pathways in a cell-specific manner to regulate the expression levels of ABCA1 and ABCG1 transporters.

Le Baiser de l'étrier, scène de la vie de garçon / par MM. Édouard Brisebarre, (Ancelot) et Eugène Nyon. [Paris, Vaudeville, 19 avril 1850]

Collection : Magasin théâtral

Fluctuaciones cíclicas y raíces unitarias en la economia española, 1850-1990

En este artículo se analiza el grado de persistencia de las fluctuaciones cíclicas en la economía española. En concreto, se estudia si el PIB y el PIB por capita de esta economía presentan una raíz unitaria. Con el fin de evitar el sesgo a aceptar raíces unitarias cuando se producen cambios en la función de tendencia, como el originado por la Guerra Civil española (1936-1939), se han aplicado varios contrastes que tienen en cuenta los cambios en la función de tendencia. Los resultados obtenidos muestran que existe una importante evidencia en el sentido que el logaritmo del PIB presenta una raíz unitaria. La principal implicación de este resultado es que los shocks sobre el producto tienen efectos permanentes en el nivel del PIB de la economía española, aun cuando esta hipótesis es más difícil de aceptar por el PIB por capita vista la evidencia contradictoria encontrada a favor de la misma.