MULTIPLE SIGNAL-TRANSDUCTION PATH WAYS REGULATE CLUSTERIN (GP-80) GENE-EXPRESSION IN MDCK CELLS

Clusterin (gp 80, apolipoprotein J TRPM-2) is a widely expressed multi functional glycoprotein. Its demonstrated and proposed functions inclu de the transport of lipids and membrane fragments, the inhibition of t he cytolytic action of the terminal complement complex and the modulat ion of cell-cell interactions. The expression of the gene is enhanced during tissue injury and remodelling and by hormone-withdrawal-induced apoptosis of prostate and mammary cells. We show here that, in the ki dney-derived epithelial cell line MDCK, clusterin mRNA is repressed by glucocorticoids and by progesterone. Treatment with epidermal growth factor also represses clusterin gene expression in MDCK cells. Incubat ion with 12-O-tetradecanoylphorbol-13-acetate, which activates protein kinase C (PKC), induces clusterin mRNA, while chelerythrine, an inhib itor of PKC, represses clusterin gene expression, suggesting that the clusterin gene responds to signalling pathways involving PKC. These re sults open up the possibility of studying the complex regulation of th e clusterin gene by multiple signal transduction pathways within a sin gle cell type, and most Importantly, of characterizing interactions be tween the individual signal transduction cascades.