Transcriptional activation of transforming growth factor beta 1 and its receptors by the Kruppel-like factor Zf9/core promoter-binding protein and Sp1 - Potential mechanisms for autocrine fibrogenesis in response to injury

We have explored the regulation of transforming growth factor beta (TGF-bet a) activity in tissue repair by examining the interactions of Zf9/core prom oter-binding protein, a Kruppel-like zinc finger transcription factor induc ed early in hepatic stellate cell (HSC) activation, with promoters for TGF- beta 1 and TGF-beta receptors, types I and II. Nuclear extracts from cultur e-activated HSCs bound avidly by electrophoretic mobility shift assay to tw o tandem GC boxes within the TGF-beta 1 promoter but minimally to a single GC box; these results correlated with transactivation by Zf9 of TGF-beta 1 promoter-reporters, Zf9 transactivated the full-length TGF-beta 1 promoter in either primary HSCs, HSC-T6 cells (an SV40-immortalized rat RSC line), H ep G2 cells, or Drosophila Schneider (S2) cells. Recombinant Zf9-GST also b ound to GC box sequences within the promoters for the types I and II TGF-be ta receptors. Both type I and type II TGF-beta receptor promoters were also transactivated by Zf9 in mammalian cells but not in S2 cells. In contrast, Spl significantly transactivated both receptor promoters in S2 cells. Thes e results suggest that (a) Zf9/core promoterbinding protein may enhance TGF -beta activity through transactivation of both the TGF-beta 1 gene and its key signaling receptors, and (b) transactivating potential of Zf9 and Sp1 t oward promoters for TGF-beta 1 and its recep tors are not identical and dep end on the cellular context.