tailieunhanh - Báo cáo khoa học: Rac upregulates tissue inhibitor of metalloproteinase-1 expression by redox-dependent activation of extracellular signal-regulated kinase signaling

The Rho-like GTPase Rac regulates distinct actin cytoskeleton changes required for adhesion, migration and invasion of cells. Tiam1 specifically activates Rac, and Rac has been shown to affect several signaling pathways in a partly cell-type-specific manner. Recently, we demonstrated that Rac activation inhibits Matrigel invasion of human carcinoma cells by tran-scriptional upregulation of tissue inhibitor of metalloproteinase-1. | ễFEBS Journal Rac upregulates tissue inhibitor of metalloproteinase-1 expression by redox-dependent activation of extracellular signal-regulated kinase signaling Rainer Engers1 Erik Springer1 Verena Kehren1 Tatjana Simic1 David A. Young2 Juliane Beier3 Lars-O. Klotz3 Ian M. Clark2 Helmut Sies3 and Helmut E. Gabbert1 1 Institute of Pathology Heinrich-Heine-University Duesseldorf Germany 2 Schoolof BiologicalSciences University of East Anglia Norwich UK 3 Institute of Biochemistry and Molecular Biology I Heinrich-Heine-University Duesseldorf Germany Keywords ERK invasion Rac reactive oxygen species Tiam1 TIMP Correspondence R. Engers Institute of Pathology Moorenstr. 5 D-40225 Duesseldorf Germany Fax 49 211 8118353 Tel 49 211 8118341 E-mail engers@ Received 21 May 2006 revised 16 August 2006 accepted 21 August 2006 doi The Rho-like GTPase Rac regulates distinct actin cytoskeleton changes required for adhesion migration and invasion of cells. Tiaml specifically activates Rac and Rac has been shown to affect several signaling pathways in a partly cell-type-specific manner. Recently we demonstrated that Rac activation inhibits Matrigel invasion of human carcinoma cells by transcriptional upregulation of tissue inhibitor of metalloproteinase-1. The purpose of the present study was to identify key mediators of Tiam1 Rac-induced tissue inhibitor of metalloproteinase-1 expression. Mutational analysis of the human tissue inhibitor of metalloproteinase-1 promoter revealed a major role for a distinct activating protein-1 site at -92 -8Ó and a minor role for an adjacent polyoma enhancer A3 site. Moreover Rac activation induced the generation of reactive oxygen species and subsequent reactive oxygen species-dependent activation of extracellular signal-regulated kinase 1 2. In contrast c-Jun N-terminal kinase and p38 mitogen-activated protein kinase activities were not affected. In line with this Tiam1 Rac-induced tissue .