Activation of extracellular signal-regulated protein kinase1,2 results in down-regulation of decorin expression in fibroblasts

Decorin is a small leucine-rich extracellular matrix proteoglycan, the expr ession of which is down-regulated in proliferating and malignantly transfor med cells. In the present study we show that the expression of decorin in f ibroblasts is suppressed by epidermal growth factor (EGF) and PMA, and that the effect of both is potently inhibited by blocking the extracellular sig nal-regulated protein kinase (ERK)1,2 signalling pathway (Raf/MEK1,2/ ERK1, 2) with the specific MAPK/ERK kinase (MEK)1,2 inhibitor, PD98059. In additi on, specific activation of ERK1,2 by adenovirus-mediated expression of cons titutively active MEK1 in dermal fibroblasts results in marked reduction in decorin mRNA abundance and production. Co-transfection of NIH-3T3 fibrobla sts with human decorin promoter/chloramphenicol acetyltransferase (CAT) con struct (pDEC-879/CAT) in combination with the expression vectors for consti tutively active Raf-1 and MEK1 markedly suppressed decorin promoter activit y. Co-transfections of human decorin promoter 5'-deletion constructs with c onstitutively active MEK1 expression vector identified the region -278 to - 188 as essential for ERK1,2 mediated down-regulation of decorin promoter ac tivity. These results show that activation of the ERK1,2 signalling pathway by a mitogenic growth factor, a tumour promoter or transformation suppress es decorin gene expression in fibroblasts, which in turn may promote prolif eration and migration of normal and malignant cells.