Mlx, a novel Max-like BHLHZip protein that interacts with the Max network of transcription factors.

Mad:Max heterodimers oppose the growth-promoting action of Myc:Max heterodimers by recruiting the mSin3-histone deacetylase (mSin3. HDAC) complex to DNA and functioning as potent transcriptional repressors. There are four known members of the Mad family that are indistinguishable in their abilities to interact with Max, bind DNA, repress transcription, and block Myc + Ras co-transformation. To investigate functional differences between Mad family proteins, we have identified additional proteins that interact with this family. Here we present the identification and characterization of the novel basic-helix-loop-helix zipper protein Mlx (Max-like protein x), which is structurally and functionally related to Max. The similarities between Mlx and Max include 1) broad expression in many tissues, 2) long protein half-life, and 3) formation of heterodimers with Mad family proteins that are capable of specific CACGTG binding. We show that transcriptional repression by Mad1:Mlx heterodimers is dependent on dimerization, DNA binding, and recruitment of the mSin3A.HDAC corepressor complex. In contrast with Max, Mlx interacts only with Mad1 and Mad4. Together, these findings suggest that Mlx may act to diversify Mad family function by its restricted association with a subset of the Mad family of transcriptional repressors.

Billin AN ，Eilers AL ，Queva C ，Ayer DE ... -  《JOURNAL OF BIOLOGICAL CHEMISTRY》

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 protein, Mlx, which interacts with Mad1 and Mad4. Here we describe the cloning and functional characterization of a new family of basic helix-loop-helix-leucine zipper heterodimeric partners for Mlx termed the Mondo family. MondoA forms homodimers weakly and does not interact with Max or members of the Myc or Mad families. MondoA and Mlx associate in vivo, and surprisingly, they are localized primarily to the cytoplasm of cultured mammalian cells. Treatment of cells with the nuclear export inhibitor leptomycin B results in the nuclear accumulation of MondoA and Mlx, demonstrating that they shuttle between the cytoplasmic and nuclear compartments rather than having exclusively cytoplasmic localization. MondoA preferentially forms heterodimers with Mlx, and this heterocomplex can bind to, and activate transcription from, CACGTG E-boxes when targeted to the nucleus via a heterologous nuclear localization signal. The amino termini of the Mondo proteins are highly conserved among family members and contain separable and autonomous cytoplasmic localization and transcription activation domains. Therefore, Mlx can mediate transcriptional repression in conjunction with the Mad family and can mediate transcriptional activation via the Mondo family. We propose that Mlx, like Max, functions as the center of a transcription factor network.

Billin AN ，Eilers AL ，Coulter KL ，Logan JS ，Ayer DE ... -  《-》

Mad3 and Mad4: novel Max-interacting transcriptional repressors that suppress c-myc dependent transformation and are expressed during neural and epidermal differentiation.

Hurlin PJ ，Quéva C ，Koskinen PJ ，Steingrímsson E ，Ayer DE ，Copeland NG ，Jenkins NA ，Eisenman RN ... -  《-》

Mlx, a new Max-like bHLHZip family member: the center stage of a novel transcription factors regulatory pathway?

Meroni G ，Cairo S ，Merla G ，Messali S ，Brent R ，Ballabio A ，Reymond A ... -  《ONCOGENE》

Mnt, a novel Max-interacting protein is coexpressed with Myc in proliferating cells and mediates repression at Myc binding sites.

Hurlin PJ ，Quéva C ，Eisenman RN 《GENES & DEVELOPMENT》