The
dioxin receptor is a gene regulatory
protein which exhibits many structural and functional similarities to
steroid hormone receptors. In this study we compare the subunit composition of two forms of the
dioxin receptor, sedimenting at approximately 9S and approximately 6S respectively, which are present in nuclear extract from wild-type Hepa 1c1c7 mouse
hepatoma cells following treatment in vivo with
dioxin. The nuclear approximately 9S receptor form contained the 90 kd
heat shock protein, hsp90. As assessed by a gel mobility shift assay, this receptor form did not bind to the
xenobiotic response element (XRE) of the target gene
cytochrome P-450 IA1. In contrast, the smaller approximately 6S receptor form did not contain any immunochemically detectable hsp90. Moreover, this receptor form specifically bound to the XRE recognition sequence. Thus, the specific
DNA binding activity of the
dioxin receptor was inhibited by association with hsp90, and the approximately 9S
dioxin receptor species could be regarded as a nonactive receptor form. Neither the approximately 9S nor the approximately 6S receptor forms were detected in nuclear extract from a
dioxin treated mutant clone of Hepa 1 that expresses a nuclear translocation deficient receptor phenotype. We conclude that activation of the
dioxin receptor is, at least, a two step process involving binding of the
ligand and dissociation of hsp90 from the
ligand-binding receptor
protein. Inhibition of the
DNA binding activity of
transcription factors by
protein--
protein interaction has also been described for several
steroid hormone receptors and for the
NF kappa B factor.(ABSTRACT TRUNCATED AT 250 WORDS)