MondoA, a novel basic helix-loop-helix-leucine zipper transcriptional activator that constitutes a positive branch of a Max-like network

Max is a common dimerization partner for a family of transcription factors (Myc, Mad [or Mxi]), and Mnt [or Rox] proteins) that regulate cell growth, proliferation, and apoptosis. We recently characterized a novel Max-like pr otein, Mlx, which interacts with Mad1 and Mad4. Here we describe the clonin g and functional characterization of a new family of basic helix-loop-helix -leucine zipper heterodimeric partners for Mlx termed the Mondo family. Mon doA forms homodimers weakly and does not interact with Max or members of th e Myc or Mad families. MondoA and Mlx associate in vivo, and surprisingly t hey are localized primarily to the cytoplasm of cultured mammalian cells. T reatment of cells with the nuclear export inhibitor leptomycin B results in the nuclear accumulation of MondoA and Mlx, demonstrating that they shuttl e between the cytoplasmic and nuclear compartments rather than having exclu sively cytoplasmic localization. MondoA preferentially forms heterodimers w ith Mlx, and this heterocomplex can bind to, and activate transcription fro m, CACGTG E-boxes when targeted to the nucleus via a heterologous nuclear l ocalization signal. The amino termini of the Mondo proteins are highly cons erved among family members and contain separable and autonomous cytoplasmic localization and transcription activation domains. Therefore, Mlx can medi ate transcriptional repression in conjunction with the Mad family and can m ediate transcriptional activation via the Mondo family. We propose that Mlx , like Max, functions as the center of a transcription factor network.