Repression of dioxin signal transduction in fibroblasts - Identification of a putative repressor associated with Arnt

Heterodimeric complexes of basic helix-loop-helix/PAS transcription factors are involved in regulation of diverse physiological phenomena such as circ adian rhythms, reaction to low oxygen tension, and detoxification, In fibro blasts, the basic helix-loop-helix/PAS heterodimer consisting of the ligand -inducible dioxin receptor and Arnt shows DNA-binding activity, and the rec eptor and Arnt are able to activate transcription when fused to a heterolog ous DNA-binding domain. However, fibroblasts are nonresponsive to dioxin wi th regard to induction mediated by the DNA response element recognized by t he receptor and Arnt. Here we demonstrate that Arnt is associated with a fi broblast-specific factor, forming a complex that is capable of binding the dioxin response element. This factor may function as a repressor since nega tive regulation of target gene induction appears to be abolished by inhibit ion of histone deacetylase activity by trichostatin A. Finally, the negativ e regulatory function of this factor appears to be restricted for dioxin si gnaling since Ar-nt was able to mediate, together with hypoxia-inducible fa ctor-la, transcriptional activation in hypoxic cells. Taken together, these data suggest that fibroblast-specific inhibition of dioxin responsiveness involves recruitment by Arnt of a cell type- and signaling pathway-specific corepressor associated with a histone deacetylase.