title: Chromatin-dependent regulation of the MMTV promoter by cAMP signaling is mediated through distinct pathways.
abstract: The nucleoprotein structure of the mouse mammary tumor virus (MMTV) promoter defines its response to cAMP signaling. A stably replicating MMTV template in highly organized chromatin is repressed in the presence of cAMP, whereas a transiently transfected template with a disorganized structure is activated. In this study, we investigate the nature of the cAMP-induced signal(s) by which these opposing responses occur to gain insight into their mechanism. We demonstrate that the transcriptional changes observed at both templates are mediated through cAMP-dependent protein kinase A (PKA). In addition, the MMTV promoter lacks a consensus cAMP response element (CRE) and neither template requires cAMP response element-binding protein (CREB) to elicit a response to cAMP signaling. However, the responses of the two templates differ mechanistically in that the CREB-binding protein p300 potentiates activation from the transient template in a manner dependent on its Cys/His-rich region 3, but does not appear to affect the repression of the replicating chromatin template. Chromatin immunoprecipitation assays show that cAMP treatment results in a decrease in acetylation of histone H4, and in multiple modifications of histone H3 at specific nucleosomes in the promoter region of the stable MMTV template. These findings suggest novel CREB-independent, chromatin-dependent pathways for transcriptional regulation by cAMP.
authors.affiliation: Department of Genetics, George Washington University, Washington, DC 20052, USA.
authors.forename: Niveen M
authors.initials: NM
authors.lastname: Mulholland
authors.forename: Sara K
authors.initials: SK
authors.lastname: Snyder
authors.forename: Sarah S
authors.initials: SS
authors.lastname: Kolla
authors.forename: Catharine L
authors.initials: CL
authors.lastname: Smith
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000107:Acetylation; D000818:Animals; D002460:Cell Line; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology; D007700:Kinetics; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics*; D051379:Mice; D009707:Nucleosomes / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D015398:Signal Transduction; D013449:Sulfonamides; D013698:Templates, Genetic; D015533:Transcriptional Activation
chemical_list: D002843:Chromatin; D004791:Enzyme Inhibitors; D006657:Histones; D007546:Isoquinolines; D009707:Nucleosomes; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D013449:Sulfonamides; D015124:8-Bromo Cyclic Adenosine Monophosphate; D003907:Dexamethasone; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide