Interleukin-6 and oncostatin M-induced growth inhibition of human A375 melanoma cells is STAT-dependent and involves upregulation of the cyclin-dependent kinase inhibitor p27/Kip1

Interleukin-6 (IL-6)-type cytokines lead to growth arrest of human A375 mel anoma cells. The present study demonstrates that this effect depends on the activation of STAT transcription factors. We observed a correlation betwee n the extent of growth inhibition exerted by IL-6, IL-6 plus soluble IL-6 r eceptor or oncostatin M (OSM) and the intensities of STAT3 and STAT1 signal s. A truncated chimeric receptor retaining only the membrane-proximal regio n of gp130, the common signal transducer of IL-6-type cytokines, did neithe r activate STATs nor mediate growth arrest of stable transfectants. These f unctions were restored by the addition of short STAT recruitment modules co mprising critical tyrosine residues from gp130 (Y767, Y814). A receptor car rying tyrosine module Y759 of gp130 effectively mediated activation of the phosphatase SHP-2 but did not alter cell growth. Overexpression of dominant negative forms of STAT3 but not STAT1 abrogated the inhibitory effect of O SM and IL-6 in A375 cells. In addition, we have identified the cyclin-depen dent kinase inhibitor p27/Kip1 as a novel target to be regulated by IL-6-ty pe cytokines. Stimulation-dependent upregulation of p27 mRNA occurred STAT3 -dependently, Also p27 protein accumulated which coincided with the disappe arance of hyperphosphorylated retinoblastoma protein in three human melanom a cell lines sensitive to IL-6-type cytokines.