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
| Autor: | Masoud Darabi, Karen Cecilia Chan, Vishwaroop Mulay, Thomas Grewal, Meritxell Reverter, Carles Rentero, Carlos Enrich, Anna Alvarez-Guaita, Monira Hoque, Kerry-Anne Rye, Peta Wood, Rose Cairns, Melanie Manetsch, Joerg Heeren |
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| Přispěvatelé: | Universitat de Barcelona |
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
MAPK/ERK pathway
Mitogen-Activated Protein Kinase 3 lcsh:Medicine Signal transduction Cardiovascular Biochemistry Transmembrane Transport Proteins Mice Molecular cell biology 0302 clinical medicine Reacció en cadena de la polimerasa Protein kinases Cricetinae Anti-apoptotic Ras signalling cascade Drug Discovery Signaling in Cellular Processes lcsh:Science ATP Binding Cassette Transporter Subfamily G Member 1 Protein Metabolism Mitogen-Activated Protein Kinase 1 0303 health sciences Multidisciplinary biology Protein Stability Kinase Mechanisms of Signal Transduction Signaling cascades Lipids 3. Good health Cell biology Polymerase chain reaction Cholesterol ABCG1 030220 oncology & carcinogenesis Medicine lipids (amino acids peptides and proteins) Colesterol ATP Binding Cassette Transporter 1 Research Article MAPK signaling cascades MAP Kinase Signaling System Lipoproteins Ras Signaling CHO Cells Protein degradation Signaling Pathways 03 medical and health sciences Cricetulus Animals Humans Protein kinase A Protein Kinase Inhibitors Biology 030304 developmental biology lcsh:R Proteins Biological Transport Lipid Metabolism Atherosclerosis Molecular biology Regulatory Proteins Proteïnes quinases Metabolism Gene Expression Regulation Proteolysis ras Proteins biology.protein ATP-Binding Cassette Transporters lcsh:Q Nuclear Receptor Signaling |
| Zdroj: | Recercat. Dipósit de la Recerca de Catalunya instname PLoS ONE, Vol 8, Iss 4, p e62667 (2013) Dipòsit Digital de la UB Universidad de Barcelona PLoS ONE |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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