Adrenocorticotropic hormone-mediated signaling cascades coordinate a cyclic pattern of steroidogenic factor 1-dependent transcriptional activation.
Steroidogenic factor 1 (SF-1) is an orphan nuclear receptor that has emerged as a critical mediator of endocrine function at multiple levels of the hypothalamic-pituitary-steroidogenic axis. Within the adrenal cortex, ACTH-dependent transcriptional responses, including transcriptional activation of several key steroidogenic enzymes within the steroid biosynthetic pathway, are largely dependent upon SF-1 action. The absence of a bona fide endogenous eukaryotic ligand for SF-1 suggests that signaling pathway activation downstream of the melanocortin 2 receptor (Mc2r) modulates this transcriptional response. We have used the chromatin immunoprecipitation assay to examine the temporal formation of ACTH-dependent transcription complexes on the Mc2r gene promoter. In parallel, ACTH-dependent signaling events were examined in an attempt to correlate transcriptional events with the upstream activation of signaling pathways. Our results demonstrate that ACTH-dependent signaling cascades modulate the temporal dynamics of SF-1-dependent complex assembly on the Mc2r promoter. Strikingly, the pattern of SF-1 recruitment and the subsequent attainment of active rounds of transcription support a kinetic model of SF-1 transcriptional activation, a model originally established in the context of ligand-dependent transcription by several classical nuclear hormone receptors. An assessment of the major ACTH-dependent signaling pathways highlights pivotal roles for the MAPK as well as the cAMP-dependent protein kinase A pathway in the entrainment of SF-1-mediated transcriptional events. In addition, the current study demonstrates that specific enzymatic activities are capable of regulating distinct facets of a highly ordered transcriptional response.
Winnay
Jonathon N
JN
Department of Molecular and Integrative Pysiology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0678, USA.
Hammer
Gary D
GD
D000107:Acetylation; D000302:Adrenal Cortex / Q000166:cytology; D000324:Adrenocorticotropic Hormone / Q000502:physiology*; D000818:Animals; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004789:Enzyme Activation; D006655:Histone Deacetylases / Q000502:physiology; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D051379:Mice; D010749:Phosphoprotein Phosphatases / Q000502:physiology; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D044103:Receptor, Melanocortin, Type 2 / Q000235:genetics / Q000502:physiology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D054339:Steroidogenic Factor 1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D015854:Up-Regulation
D006657:Histones; D018398:Homeodomain Proteins; D044103:Receptor, Melanocortin, Type 2; D018160:Receptors, Cytoplasmic and Nuclear; D054339:Steroidogenic Factor 1; D014157:Transcription Factors; C515058:steroidogenic factor 1, mouse; D000324:Adrenocorticotropic Hormone; D017868:Cyclic AMP-Dependent Protein Kinases; D010749:Phosphoprotein Phosphatases; D010744:Phosphoric Monoester Hydrolases; D006655:Histone Deacetylases