Noncanonical BMP Signaling Regulates Cyclooxygenase-2 Transcription

• DOI: 10.1210/me.2010-0515
• Publication Date: 2011-03-25T02:31:23Z
• Authors: Antonio R. G. Sus...; Cristina Gamell; Edgardo Rodríguez...; Maria José Ortuño; Ramon Bartrons; José Luis Rosa; Francesc Ventura
• Keywords: 0303 health sciences; Proto-Oncogene Proteins c-jun; Pyridines; Skull; Imidazoles; Bone Morphogenetic Protein 2; Core Binding Factor Alpha 1 Subunit; Mesenchymal Stem Cells; Response Elements; Cell Line; Tissue Culture Techniques; Mice; 03 medical and health sciences; Pyrimidines; Gene Expression Regulation; Cyclooxygenase 2; Animals; Pyrazoles; Regulatory Elements, Transcriptional; Enzyme Inhibitors; Promoter Regions, Genetic; Signal Transduction

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.