title: Transcriptional regulation of the chemokine co-receptor CCR5 by the cAMP/PKA/CREB pathway.
abstract: The cyclic adenosine monophosphate (cAMP)-dependent signaling pathway directs the expression of several genes involved in diverse neuroendocrine, immune, metabolic, and developmental pathways. The primary effectors of this pathway are members of the cAMP response element binding (CREB) family of transcription factors, in particular the CREB-1 and cAMP response element modulator (CREM). Both these genes encode alternative splice variants that serve as activators or repressors in a context- and position-specific manner. Although the β-chemokine receptor CC chemokine receptor 5 (CCR5) has been identified on progenitor cells in the bone marrow, the regulatory mechanisms orchestrating its expression are not fully understood. Previous reports have identified putative cAMP response elements in the CCR5 promoter and have described a suppressive role of cAMP in CCR5 expression. In this study, the CD34+CD4+CCR5+ human bone marrow progenitor cell line TF-1 was used to investigate the detailed kinetics of CCR5 transcription in response to the elevation of intracellular cAMP levels and the underlying molecular events. We hypothesize that CCR5 transcription follows an asymmetrical sinusoidal pattern in TF-1 cells that parallels a protein kinase A-dependent alternating change in the ratio of activator pCREB-1-α,Δ to repressor pCREM-α,β isoforms. However, elevated CCR5 mRNA levels do not correlate with enhancement in infectivity with respect to the R5 human immunodeficiency virus type 1 (HIV-1) strain. Our results lend critical insight into the precise mechanism governing the cAMP-CCR5 axis in progenitor cells and pose interesting questions regarding its functional role in HIV-1 infection.
authors: Department of Microbiology and Immunology, Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, 245 N. 15th Street, MS# 1013A, Philadelphia, Pennsylvania 19102, USA.
authors: Anupam
authors: A
authors: Banerjee
authors: Vanessa
authors: V
authors: Pirrone
authors: Brian
authors: B
authors: Wigdahl
authors: Michael R
authors: MR
authors: Nonnemacher
mesh_terms: D018952:Antigens, CD34 / Q000276:immunology; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology; D015704:CD4 Antigens / Q000276:immunology; D018929:Cell Culture Techniques; D002460:Cell Line; D002467:Cell Nucleus / Q000276:immunology / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism* / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism* / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D016655:HIV Core Protein p24; D015497:HIV-1 / Q000472:pathogenicity; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012313:RNA / Q000378:metabolism; D019713:Receptors, CCR5 / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013234:Stem Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology; D013449:Sulfonamides / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D018952:Antigens, CD34; D015704:CD4 Antigens; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D016655:HIV Core Protein p24; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D019713:Receptors, CCR5; D013449:Sulfonamides; D005576:Colforsin; D012313:RNA; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide