title: CCAAT-enhancer-binding protein beta activation of MMP-1 gene expression in SW1353 cells: independent roles of extracellular signal-regulated and p90/ribosomal S6 kinases.
abstract: CCAAT-enhancer-binding protein beta (CEBPB) is a pluripotent transcription factor that controls inflammation, proliferation, and differentiation. We recently reported a role for CEBPB during matrix metalloproteinase (MMP) gene expression, but the mechanisms involved are poorly understood. To address this we interrogated CEBPB-dependent MMP-1 and MMP-13 gene activation in the SW1353 chondrosarcoma cell line, a well-established model of MMP gene regulation in mesenchymal cells. IL-1B treatment increased CEBPB expression in SW1353 cells over a 24-h period and knockdown of CEBPB with shRNA abrogated IL-1B-dependent MMP-1 and MMP-13 gene activation. Exogenous expression of the CEBPB isoforms LAP1 or LAP2 was sufficient to induce MMP-1 mRNA levels comparable to IL-1B-induced expression, while the truncated LIP isoform repressed IL-1B-induced MMP-1. Although exogenous CEBPB expression induced MMP-13 mRNA, the response was less robust than was observed for MMP-1. CEBPB is activated by the extracellular-regulated kinases (ERK) and RSK kinases in response to oncogenes and growth factors. We found that the MEK inhibitor U0126 and the RSK inhibitor BI-D1870 both reduced IL-1B-dependent MMP-1 gene expression in SW1353 cells. Although ERK is known to phosphorylate CEBPB on threonine 235, this residue was not required for CEBPB-dependent activation of MMP-1. In contrast, the RSK target serine 321 was required for LAP1 and LAP2-dependent activation of MMP-1. These findings establish CEBPB as a critical intermediate for IL-1B-dependent MMP gene activation and assign specific roles for the ERK and RSK kinases in this pathway.
authors.affiliation: Research Service, Department of Veterans Affairs, White River Junction, Vermont 05009, USA.
authors.forename: Brenda L
authors.initials: BL
authors.lastname: Petrella
authors.forename: David A
authors.initials: DA
authors.lastname: Armstrong
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Vincenti
mesh_terms: D001859:Bone Neoplasms / Q000201:enzymology* / Q000235:genetics; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002813:Chondrosarcoma / Q000201:enzymology* / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism*; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; C545012:CEBPB protein, human; D053583:Interleukin-1beta; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D048049:Extracellular Signal-Regulated MAP Kinases; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1