Jun N-terminal kinase 1 mediates transcriptional induction of matrix metalloproteinase 9 expression.
Tumor cell invasion and metastasis require precise coordination of adherence to extracellular matrix (ECM) and controlled degradation of its components. Invasive cells secrete proteolytic enzymes known as matrix metalloproteinases (MMPs) which degrade specific basement membrane molecules. Expression of these enzymes is regulated by multiple signaling mechanisms, including the mitogen-activated protein kinase (MAPK) pathway. One of the terminal effectors of this signaling cascade is jun N-terminal kinase 1 (JNK1) which phosphorylates the transcription factor c-jun, a component of the AP-1 complex. MMP-9 expression is regulated by two well-characterized AP-1 sites in the promoter of this gene. To determine how JNK1 activity regulated MMP-9 expression in human squamous cell carcinoma lines, we overexpressed this kinase in SCC25 cells. JNK1 overexpression induced MMP-9 protein levels and activity in this cell line. Elevated MMP-9 expression correlated with increased invasion of reconstituted basement membranes by JNK1-overexpressing clones. Site-directed mutagenesis of the MMP-9 promoter revealed that JNK1 cooperated with its transcription factor target c-jun to increase MMP-9 expression at the transcriptional level via the proximal AP-1 site. These results suggest that elevated JNK1 expression may contribute to increased MMP-9 activity and ECM invasion by tumor cells.
Crowe
D L
DL
Center for Craniofacial Molecular Biology, University of Southern California, 2250 Alcazar Street, Los Angeles, CA 90033, USA. dcrowe@hsc.usc.edu
Tsang
K J
KJ
Shemirani
B
B
D001665:Binding Sites; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000378:metabolism; D015500:Chloramphenicol O-Acetyltransferase / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D009361:Neoplasm Invasiveness; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D015500:Chloramphenicol O-Acetyltransferase; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9