Drosophila single-minded, which acts as a positive master gene regulator in central nervous system midline formation in Drosophila, its two mouse homologs SIM1 and SIM2, and the mammalian aryl hydrocarbon receptor (AHR) and aryl hydrocarbon receptor nuclear translocator (ARNT) proteins are members of the basic-helix-loop-helix.PAS family of transcription factors. In the yeast two-hybrid system, we demonstrate strong constitutive interaction of ARNT with SIM1 and SIM2 and fully ligand-dependent interaction of ARNT with AHR. Both the helix-loop-helix and the PAS regions of SIM1 and of ARNT are required for efficient heterodimerization. SIM1 and SIM2 do not form homodimers, and they do not interact with AHR. We also failed to detect homodimerization of ARNT. The interaction of ARNT with SIM1 was confirmed with in vitro synthesized proteins. Like AHR, in vitro synthesized SIM1 associates with the 90-kDa heat shock protein. SIM1 inhibits binding of the AHR.ARNT dimer to the xenobiotic response element in vitro. Introduction of SIM1 into hepatoma cells inhibits transcriptional transactivation by the endogenous AHR.ARNT dimer. The mouse SIM1. ARNT dimer binds only weakly to a proposed DNA target for the Drosophila SIM.ARNT dimer. In adult mice mRNA for SIM1 was expressed in lung, skeletal muscle, and kidney, whereas the mRNA for SIM2 was found in the latter two. ARNT is also expressed in these organs. Thus mouse SIM1 and SIM2 are novel heterodimerization partners for ARNT in vitro, and they may function both as positive and negative transcriptional regulators in vivo, during embryogenesis and in the adult organism.
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