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 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/-86 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 inhibitor of metalloproteinase-1 expression as well as Tiam1/Rac-induced binding of nuclear extracts to the activating protein-1 site at -92/-86 were inhibited by catalase and by specific inhibitors of the extracellular signal-related kinase-1,2 activators, mitogen-activated protein kinase kinase-1 and mitogen-activated protein kinase kinase-2 (PD098059, U0126). In conclusion, Rac-induced transcriptional upregulation of tissue inhibitor of metalloproteinase-1 is mediated by reactive oxygen species-dependent activation of extracellular signal-related kinase-1,2 and by transcription factors of the activating protein-1 family.
Engers
Rainer
R
Institute of Pathology, Heinrich-Heine-University, Duesseldorf, Germany. engers@med.uni-duesseldorf.de
Springer
Erik
E
Kehren
Verena
V
Simic
Tatjana
T
Young
David A
DA
Beier
Juliane
J
Klotz
Lars-O
LO
Clark
Ian M
IM
Sies
Helmut
H
Gabbert
Helmut E
HE
D000970:Antineoplastic Agents / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D020662:Guanine Nucleotide Exchange Factors / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010084:Oxidation-Reduction; D011401:Promoter Regions, Genetic; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D015854:Up-Regulation; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000502:physiology*
D000970:Antineoplastic Agents; D020662:Guanine Nucleotide Exchange Factors; D017382:Reactive Oxygen Species; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C087334:TIAM1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D018808:Transcription Factor AP-1; D048052:Mitogen-Activated Protein Kinase 3; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins