Human neutrophil lactoferrin trans-activates the matrix metalloproteinase 1 gene through stress-activated MAPK signaling modules.
It has been proposed that human neutrophil lactoferrin (Lf) could be involved in gene expression as a DNA-binding protein after its translocation into the nucleus. However, the molecular basis of Lf action has not been defined, and Lf-regulated target genes have not been identified. We report here that overexpressed Lf functions as a specific trans-activator of matrix metalloproteinase 1 (MMP1) gene, and that induction of this AP-1-responsive gene is mediated via the stress-activated MAPK signaling modules. Transactivation of the MMP1 promoter by overexpressed Lf requires the presence of an AP-1 binding site. In gel shift experiments, Lf did not interact directly with AP-1-containing fragments of the MMP1 promoter. However, nuclear extracts from Lf-expressing cells contained increased levels of proteins that bound to AP-1 elements. This Lf-induced AP-1 DNA binding activity was reduced by a p38 MAPK inhibitor. Inhibitors of the MEK kinases had little effect on Lf-induced AP-1. However, expression of dominant-negative MKK4 or JNK1 inhibited Lf-induced gene expression. The JNK activity stimulated by Lf correlates with the enhanced AP-1 binding ability. These findings demonstrate that the Lf-induced activation of AP-1 is mediated via JNK and p38 MAPK pathways.
Oh
S M
SM
Division of Life Sciences, Graduate School of Biotechnology, Korea University, Seoul 136-701, Korea.
Hahm
D H
DH
Kim
I H
IH
Choi
S Y
SY
D016475:3T3 Cells; D000818:Animals; D019556:COS Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D007781:Lactoferrin / Q000494:pharmacology*; D048670:MAP Kinase Kinase 4; D020781:Matrix Metalloproteinase 1 / Q000235:genetics*; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D009504:Neutrophils / Q000502:physiology*; D011401:Promoter Regions, Genetic; D015534:Trans-Activators / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases
D015534:Trans-Activators; D018808:Transcription Factor AP-1; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human; C482562:Map2k4 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; D007781:Lactoferrin; D020781:Matrix Metalloproteinase 1