The p38 SAPK pathway regulates the expression of the MMP-9 collagenase via AP-1-dependent promoter activation.
The invasive phenotype of cancers critically depends on the expression of proteases such as the M(R) 92,000 type IV collagenase (MMP-9). Several growth factors and oncogenes were found to increase promoter activity and as a consequence protease expression. This frequently requires the activation of the transcription factor AP-1 by signal transduction cascades such as the ERK and JNK pathways. We have previously demonstrated that the tumor promoter TPA can induce MMP-9 expression via a third signaling cascade, the p38 pathway. Considering that TPA is a potent activator of AP-1, we hypothesized that this transcription factor might also be required for p38 pathway-dependent MMP-9 regulation. While dominant negative p38 and MKK-6 mutants reduced MMP-9 promoter activity in CAT assays, a construct encoding an activating mutation in the MKK-6 protein potently stimulated it. This was mediated via 144 bp of the 5'flanking region of the wild-type promoter, which contains an AP-1 site at -79. Both point mutations in this motif and the expression of a c-jun protein lacking its transactivation domain and therefore acting as a dominant negative AP-1 mutant abrogated MKK-6-dependent promoter stimulation. Finally SB 203580, a specific p38 pathway inhibitor, reduced MMP-9 expression/secretion and in vitro invasion of cancer cells. Thus, our results provide evidence that also the third SAPK/MAPK signaling cascade, the p38 signal transduction pathway, stimulates MMP-9 expression in an AP-1-dependent fashion.
Simon
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C
Department of Otolaryngology, Head and Neck Surgery, The University of Tuebingen, Tuebingen, 72076, Germany. csimon1407@aol.com
Simon
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M
Vucelic
G
G
Hicks
M J
MJ
Plinkert
P K
PK
Koitschev
A
A
Zenner
H P
HP
D001483:Base Sequence / Q000235:genetics; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D002273:Carcinogens / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D017930:Genes, Reporter; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D048669:MAP Kinase Kinase 6; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000502:physiology; D009361:Neoplasm Invasiveness / Q000235:genetics*; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D020079:Terminal Repeat Sequences / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D048051:p38 Mitogen-Activated Protein Kinases
D002273:Carcinogens; D004791:Enzyme Inhibitors; D007093:Imidazoles; D020033:Protein Isoforms; D016755:Proto-Oncogene Proteins c-jun; D011725:Pyridines; D018808:Transcription Factor AP-1; C431843:tris(2-pyridylmethyl)amine; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048669:MAP Kinase Kinase 6; C482566:MAP2K6 protein, human; D020780:Matrix Metalloproteinase 9; C093642:SB 203580