cAMP regulates expression of the cyclic nucleotide transporter MRP4 (ABCC4) through the EPAC pathway
| Autor: | Sebastian Zang, Yvonne Schaletzki, Susanne Bröderdorf, Heyo K. Kroemer, Gabriele Jedlitschky, Markus Grube |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Vascular smooth muscle
ABCC4 Cyclic nucleotide chemistry.chemical_compound Downregulation and upregulation Cyclic AMP Genetics Transcriptional regulation Humans RNA Small Interfering General Pharmacology Toxicology and Pharmaceutics Protein kinase A Molecular Biology Cells Cultured Genetics (clinical) Muscle Cells biology Activator (genetics) Kinase Muscle Smooth Up-Regulation Cell biology Gene Expression Regulation chemistry biology.protein Molecular Medicine Multidrug Resistance-Associated Proteins HeLa Cells Signal Transduction |
| Zdroj: | Pharmacogenetics and Genomics. 24:522-526 |
| ISSN: | 1744-6872 |
| DOI: | 10.1097/fpc.0000000000000084 |
| Popis: | Multidrug resistance protein 4 (MRP4/ABCC4) has been established as an independent regulator of cyclic AMP (cAMP) levels particularly in vascular smooth muscle cells and in hematopoietic cells. Here, we assessed whether cAMP in turn regulates MRP4. A significant upregulation of MRP4 mRNA and protein by long-term treatment with cAMP-enhancing agents was observed in HeLa cells, smooth muscle cells, and megakaryoblastic leukemia M07e cells. This upregulation was not affected by inhibition of protein kinase A, but could be reverted by inhibitors and siRNA of an alternative cAMP-signaling route involving exchange proteins activated by cyclic AMP (EPAC) and mitogen-activated protein kinases. A selective EPAC activator could equally induce MRP4. The transcriptional regulation was confirmed in a luciferase reporter gene assay using a vector containing a 1494-bp fragment of the promoter region of the MRP4/ABCC4 gene. Our results suggest that enhanced cAMP levels upregulate MRP4 expression, which can result in increased cAMP efflux. |
| Databáze: | OpenAIRE |
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