Noncanonical BMP Signaling Regulates Cyclooxygenase-2 Transcription

• Published in: Molecular endocrinology (Baltimore, Md.) Vol. 25; no. 6; pp. 1006 - 1017
• Main Authors: Susperregui, Antonio R. G, Gamell, Cristina, Rodríguez-Carballo, Edgardo, Ortuño, Maria José, Bartrons, Ramon, Rosa, José Luis, Ventura, Francesc
• Format: Journal Article
• Language: English
• Published: United States Endocrine Society 01-06-2011; Oxford University Press
• Subjects: Animals; Bone Morphogenetic Protein 2 - antagonists & inhibitors; Bone Morphogenetic Protein 2 - genetics; Bone Morphogenetic Protein 2 - pharmacology; Cell Line; Core Binding Factor Alpha 1 Subunit - genetics; Core Binding Factor Alpha 1 Subunit - metabolism; Cyclooxygenase 2 - genetics; Cyclooxygenase 2 - metabolism; Enzyme Inhibitors - pharmacology; Gene Expression Regulation; Imidazoles - pharmacology; Mesenchymal Stem Cells - drug effects; Mesenchymal Stem Cells - metabolism; Mice; Original Research; p38 Mitogen-Activated Protein Kinases - metabolism; Promoter Regions, Genetic; Proto-Oncogene Proteins c-jun - genetics; Proto-Oncogene Proteins c-jun - metabolism; Pyrazoles - pharmacology; Pyridines - pharmacology; Pyrimidines - pharmacology; Regulatory Elements, Transcriptional; Response Elements; Signal Transduction - genetics; Skull - drug effects; Skull - metabolism; Tissue Culture Techniques; Transcription, Genetic
• ISSN: 0888-8809; 1944-9917
• DOI: 10.1210/me.2010-0515

BMP transcriptional responses on Cox2 promoter are mediated through cooperative effects between the canonical and the p38-dependent BMP signaling pathways.
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.