| Description |
Max functions at the center of a transcriptional network involving interaction with either the Myc family of transcriptional activators or the Mad family of transcriptional repressors. This Myc/Max/Mad network is a key regulator of cell growth, proliferation and the transition to differentiation. Members of this network contain the basic helix-loop-helix leucine zipper domain (BHLHZip) that mediates dimerization and DNA binding to the CACGTG subclass of E-box elements. Mlx, a novel Max-like protein, has been recently characterized. Mlx interacts with a subset of the Mad family members, Mad1 and Mad4. Like Max, Mlx is a widely and stably expressed BHLHZip protein that heterodimerizes with Mad1 and Mad4 to bind the CACGTG binding sites. Mad1:Mlx heterodimers can repress transcription and like Mad1:Max heterodimers, this repression is dependent on dimerization, DNA binding, and recruitment of the Sin3 corepressor complex. Like Max, Mlx also interacts with a family of transcriptional activators, the Mondo family of BHLHZip proteins. MondoA does not readily form homodimers, but preferentially heterodimerizes with Mlx and binds CACGTG E-boxes. In contrast to the nuclear localization of Myc, Max and Mad, MondoA and Mlx localize to the cytoplasm of all mammalian cell lines tested. MondoA:Mlx can activate transcription when targeted to the nucleus by a heterologous nuclear localization signal. Regulation of MondoA and Mlx subcellular localization appears to be a critical means of regulating the transcriptional activity of the heterodimer. MondoA and Mlx contain a C-terminal conserved region that plays a role in cytoplasmic localization. This domain, found only in Mlx and Mondo family members, is also a novel heterodimerization domain. Dimerization of MondoA and Mlx inactivates the cytoplasmic localization activity of this DCL (dimerization and cytoplasmic localization) domain. The heterodimer remains cytoplasmic due to the activity of a N-terminal cytoplasmic localization domain within MondoA. This domain, which includes a CRM1-dependent nuclear export signal, a 14-3-3 binding site and other cytoplasmic localization activity, is inactivated presumably by a signaling event. This regulatory complexity suggests that MondoA:Mlx regulates an important cellular function. |
