title: cAMP regulates expression of the cyclic nucleotide transporter MRP4 (ABCC4) through the EPAC pathway.
abstract: 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.
authors.affiliation: Department of Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine, Greifswald, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Bröderdorf
authors.forename: Sebastian
authors.initials: S
authors.lastname: Zang
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Schaletzki
authors.forename: Markus
authors.initials: M
authors.lastname: Grube
authors.forename: Heyo K
authors.initials: HK
authors.lastname: Kroemer
authors.forename: Gabriele
authors.initials: G
authors.lastname: Jedlitschky
mesh_terms: D002478:Cells, Cultured; D000242:Cyclic AMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics* / Q000378:metabolism*; D032342:Muscle Cells / Q000378:metabolism*; D009130:Muscle, Smooth / Q000166:cytology* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation
chemical_list: D000242:Cyclic AMP; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D034741:RNA, Small Interfering; C073492:ABCC4 protein, human