Tumor-derived EMMPRIN (extracellular matrix metalloproteinase inducer) stimulates collagenase transcription through MAPK p38.
EMMPRIN (extracellular matrix metalloproteinase inducer) stimulates fibroblast metalloproteinases (MMP) 1, 2 and 3 (Kataoka et al. (1993) Cancer Res. 53, 3154-3158). Here we focus on MMP-1, showing that in lung tumors, MMP-1's cognate mRNA is strongly expressed in stromal fibroblasts adjacent to EMMPRIN-expressing tumor cells. In vitro, EMMPRIN upregulates MMP-1 mRNA expression in a concentration-dependent manner, with a peak accumulation at 24 h. The response is genistein-sensitive, suggesting it is dependent on tyrosine kinase activity. Analysis of tyrosine phosphorylation-dependent MAP kinases ERK 1/2, SAPK/JNK, and p38 showed that the activity of p38 but not that of the other 2 kinases was elevated in response to EMMPRIN. That p38 activity was required for EMMPRIN stimulation of MMP-1 was evident from results showing that the p38 inhibitor SB203580 blocked this response. This is the first available information regarding the mechanism by which tumor-associated molecules upregulate MMP synthesis in stromal fibroblasts.
Lim
M
M
Department of Anatomy, University of California, San Francisco 94143-0452, USA. mslim@itsa.ucsf.edu
Martinez
T
T
Jablons
D
D
Cameron
R
R
Guo
H
H
Toole
B
B
Li
J D
JD
Basbaum
C
C
D015703:Antigens, CD; D000951:Antigens, Neoplasm; D051926:Basigin; D014408:Biomarkers, Tumor; D001980:Bronchi / Q000201:enzymology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000235:genetics*; D002460:Cell Line; D017364:Collagenases / Q000235:genetics*; D004847:Epithelial Cells / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007700:Kinetics; D008168:Lung / Q000378:metabolism; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics*; D020781:Matrix Metalloproteinase 1; D008562:Membrane Glycoproteins / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014158:Transcription, Genetic; D048051:p38 Mitogen-Activated Protein Kinases
D015703:Antigens, CD; D000951:Antigens, Neoplasm; C497886:BSG protein, human; D014408:Biomarkers, Tumor; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D051926:Basigin; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D017364:Collagenases; D020781:Matrix Metalloproteinase 1