title: Noncanonical BMP signaling regulates cyclooxygenase-2 transcription.
abstract: Activation of p38 MAPK has been shown to be relevant for a number of bone morphogenetic protein (BMP) physiological effects. We report here the involvement of noncanonical phosphorylated mothers against decapentaplegic (Smad) signaling in the transcriptional induction of Cox2 (Ptgs2) by BMP-2 in mesenchymal cells and organotypic calvarial cultures. We demonstrate that different regulatory elements are required for regulation of Cox2 expression by BMP-2: Runt-related transcription factor-2 and cAMP response element sites are essential, whereas a GC-rich Smad binding element is important for full responsiveness. Efficient transcriptional activation requires cooperation between transcription factors because mutation of any element results in a strong decrease of BMP-2 responsiveness. BMP-2 activation of p38 leads to increased recruitment of activating transcription factor-2, Runx2, Smad, and coactivators such as p300 at the responsive sites in the Cox2 proximal promoter. We demonstrate, by either pharmacological or genetic analysis, that maximal BMP-2 effects on Cox2 and JunB expression require the function of p38 and its downstream effector mitogen/stress-activated kinase 1. Altogether our results strongly suggest that cooperative effects between canonical and noncanonical BMP signaling allow the fine-tuning of BMP transcriptional responses on specific target genes.
authors: Departament de Ciències Fisiològiques II, Bellvitge Biomedical Research Institute, C/ Feixa Llarga s/n., L'Hospitalet de Llobregat, Universitat de Barcelona, E-08907 Barcelona, Spain.
authors: Antonio R G
authors: AR
authors: Susperregui
authors: Cristina
authors: C
authors: Gamell
authors: Edgardo
authors: E
authors: Rodríguez-Carballo
authors: Maria José
authors: MJ
authors: Ortuño
authors: Ramon
authors: R
authors: Bartrons
authors: José Luis
authors: JL
authors: Rosa
authors: Francesc
authors: F
authors: Ventura
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000494:pharmacology*; D002460:Cell Line; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D007093:Imidazoles / Q000494:pharmacology; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D050436:Regulatory Elements, Transcriptional; D020218:Response Elements; D015398:Signal Transduction / Q000235:genetics*; D012886:Skull / Q000187:drug effects / Q000378:metabolism; D046509:Tissue Culture Techniques; D014158:Transcription, Genetic; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D050659:Core Binding Factor Alpha 1 Subunit; D004791:Enzyme Inhibitors; D007093:Imidazoles; D016755:Proto-Oncogene Proteins c-jun; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; C493716:Runx2 protein, mouse; C516138:dorsomorphin; D051546:Cyclooxygenase 2; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580