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 circadian rhythms, reaction to low oxygen tension, and detoxification. In fibroblasts, the basic helix-loop-helix/PAS heterodimer consisting of the ligand-inducible dioxin receptor and Arnt shows DNA-binding activity, and the receptor and Arnt are able to activate transcription when fused to a heterologous DNA-binding domain. However, fibroblasts are nonresponsive to dioxin with regard to induction mediated by the DNA response element recognized by the receptor and Arnt. Here we demonstrate that Arnt is associated with a fibroblast-specific factor, forming a complex that is capable of binding the dioxin response element. This factor may function as a repressor since negative regulation of target gene induction appears to be abolished by inhibition of histone deacetylase activity by trichostatin A. Finally, the negative regulatory function of this factor appears to be restricted for dioxin signaling since Arnt was able to mediate, together with hypoxia-inducible factor-1alpha, 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.
Gradin
K
K
Department of Cell and Molecular Biology, Karolinska Institute, S-171 77 Stockholm, Sweden. katarina.gradin@cmb.ki.se
Toftgârd
R
R
Poellinger
L
L
Berghard
A
A
D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D001483:Base Sequence; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism; D004147:Dioxins / Q000378:metabolism / Q000494:pharmacology*; D004790:Enzyme Induction; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured
C497396:ARNT protein, human; D017931:DNA Primers; D004268:DNA-Binding Proteins; D004147:Dioxins; C497442:HIF1A protein, human; D006877:Hydroxamic Acids; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D018336:Receptors, Aryl Hydrocarbon; D011994:Recombinant Proteins; D014157:Transcription Factors; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; C012589:trichostatin A; D019363:Cytochrome P-450 CYP1A1