title: A novel role for c-Myc in G protein-coupled receptor kinase 4 (GRK4) transcriptional regulation in human kidney proximal tubule cells.
abstract: The G protein-coupled receptor kinase 4 (GRK4) negatively regulates the dopaminergic system by desensitizing the dopamine-1-receptor. The expressional control of GRK4 has not been reported, but here we show that the transcription factor c-Myc binds to the promoter of GRK4 and positively regulates GRK4 protein expression in human renal proximal tubule cells (RPTCs). Addition of phorbol esters to RPTCs not only increased c-Myc binding to the GRK4 promoter but also increased both phospho-c-Myc and GRK4 expression. The phorbol ester-mediated increase in GRK4 expression was completely blocked by the c-Myc inhibitor, 10074-G5, indicating that GRK4 is downstream of phospho-c-Myc. The autocrine production of angiotensin II (Ang II) in RPTCs increased the phosphorylation and activation of c-Myc and subsequently GRK4 expression. 3-Amino-4-thio-butyl sulfonate, an inhibitor of aminopeptidase A, increased RPTC secretion of Ang II. 3-Amino-4-thio-butyl sulfonate or Ang II increased the expression of both phospho-c-Myc and GRK4, which was blocked by 10074-G5. Blockade of the Ang II type 1 receptor with losartan decreased phospho-c-Myc and GRK4 expression. Both inhibition of c-Myc activity and blockade of Ang II type 1 receptor restored the coupling of dopamine-1-receptor to adenylyl cyclase stimulation in uncoupled RPTCs, whereas phorbol esters or Ang II caused the uncoupling of normally coupled RPTCs. We suggest that the Ang II type 1 receptor impairs dopamine-1-receptor function via c-Myc activation of GRK4. This novel pathway may be involved in the increase in blood pressure in hypertension that is mediated by increased activity of the renin-angiotensin system and decreased activity of the renal dopaminergic system.
authors.affiliation: Department of Pathology, University of Virginia Health System, Charlottesville, VA 22908, USA. jjg5b@virginia.edu
authors.forename: John J
authors.initials: JJ
authors.lastname: Gildea
authors.forename: Hanh T
authors.initials: HT
authors.lastname: Tran
authors.forename: Robert E
authors.initials: RE
authors.lastname: Van Sciver
authors.forename: Dora
authors.initials: D
authors.lastname: Bigler Wang
authors.forename: Julia M
authors.initials: JM
authors.lastname: Carlson
authors.forename: Robin A
authors.initials: RA
authors.lastname: Felder
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D054771:G-Protein-Coupled Receptor Kinase 4 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019808:Losartan / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D010703:Phorbol Esters / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D011954:Receptors, Dopamine / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*
chemical_list: C534883:10074-G5; C489427:MYC protein, human; D010069:Oxadiazoles; D010703:Phorbol Esters; D016271:Proto-Oncogene Proteins c-myc; D044140:Receptor, Angiotensin, Type 1; D011954:Receptors, Dopamine; D000804:Angiotensin II; D054771:G-Protein-Coupled Receptor Kinase 4; C517855:GRK4 protein, human; D019808:Losartan