Tumor-derived EMMPRIN (extracellular matrix metalloproteinase inducer) stimulates collagenase transcription through MAPK p38

EMMPRIN (extracellular matrix metalloproteinase inducer) stimulates fibrobl ast metalloproteinases (MMP) 1, 2 and 3 (Kataoka et al, (1993) Cancer Res. 53, 3154-3158), Here me focus on MMP-1, showing that in lung tumors, MMP-1' s cognate mRNA is strongly expressed in stromal fibroblasts adjacent to EMM PRIN-expressing tumor cells. In vitro, EMMPRIN upregulates MMP-1 mRNA expre ssion in a concentration-dependent manner, with a peak accumulation at 24 h , The response is genistein-sensitive, suggesting it is dependent on tyrosi ne kinase activity. Analysis of tyrosine phosphorylation-dependent MAP kina ses ERK 1/2, SAPK/JNK, and p38 showed that the activity of p38 but not that of the other 2 kinases,vas elevated in response to EMMPRIN. That p38 activ ity mas required for EMMPRIN stimulation of MMP-1 mas evident from results showing that the p38 inhibitor SB203580 blocked this response. This is the first available information regarding the mechanism by which tumor-associat ed molecules upregulate MMP synthesis in stromal fibroblasts, (C) 1998 Fede ration of European Biochemical Societies.