SEPARATE SIGNALING MECHANISMS ARE INVOLVED IN THE CONTROL OF STAT PROTEIN-ACTIVATION AND GENE-REGULATION VIA THE INTERLEUKIN-6 RESPONSE ELEMENT BY THE BOX-3 MOTIF OF GP130

The cytoplasmic receptor sequences required for the transcriptional co ntrol via the IL-6 response element (IL-6RE) and the hematopoietin rec eptor response element (HRRE) in hepatoma cells were defined by transi ent expression of wild-type and mutant granulocyte-colony stimulating factor receptor-gp130 chimeric receptors. gp130 generated two separate transcriptional signals, one of which was directed to IL-6RE and requ ired an intact box 3 motif, and another, which was directed to HRRE an d was box 3-independent. The activation of DNA-binding of STAT3 requir ed the same gp130 domains as the IL-6RE response. A box 3-independent activation of STAT proteins was achieved by overexpression of the kina ses JAK2 or TYK2. The increase in the DNA-binding activity of STAT pro teins, however, did not result in a corresponding increase in transcri ption via either IL-6RE or HRRE. The data indicate that activation of the DNA-binding potential of STAT proteins via gp130 is not sufficient to achieve transcriptional up-regulation of specific target genes.