Alternative titles; symbols
HGNC Approved Gene Symbol: MLX
Cytogenetic location: 17q21.2 Genomic coordinates (GRCh38): 17:42,567,100-42,573,203 (from NCBI)
Members of the basic helix-loop-helix leucine zipper (bHLH-ZIP) family are transcription factors with roles in proliferation, determination, and differentiation (e.g., MAX, 154950). By searching sequence databases with a mouse Tcfl4 cDNA, Bjerknes and Cheng (1996) identified several TCFL4 expressed sequence tags derived from a variety of human tissues, and a 46-kb cosmid clone (GenBank U34879) containing the human TCFL4 gene. The predicted TCFL4 protein contains a basic helix-loop-helix domain and a leucine zipper domain. RT-PCR detected mouse Tcfl4 expression in all tissues examined.
In a 2-hybrid screen to identify Mad1 (602686)-interacting proteins, Billin et al. (1999) identified TCFL4 as MLX, a bHLH-ZIP protein that is structurally and functionally related to MAX. The predicted amino acid sequence of MLX is conserved at all positions that define the bHLH-ZIP class of transcription factors and is most similar to that of MAX, sharing approximately 50% identity in the bHLH-ZIP domains. The 244-amino acid human and mouse MLX proteins differ at only 4 amino acid positions. Billin et al. (1999) showed that transcriptional repression by Mad1:Mlx heterodimers is dependent on dimerization, DNA binding, and recruitment of the Sin3A (607776)-histone deacetylase (see 601241) corepressor complex. Their findings suggested that MLX may act to diversify Mad family function by its restricted association with a subset of the Mad family of transcriptional repressors.
Williams-Beuren syndrome (WBS; 194050) is a developmental disorder associated with haploinsufficiency of multiple genes at 7q11.23. Cairo et al. (2001) reported that WBSCR14 (605678) formed heterodimers with MLX to bind the DNA sequence CACGTG. Like MAX, MLX has no intrinsic transcriptional activity, but its association with MAD1, MAD4, MNT (603039), or WBSCR14 can repress E-box-dependent transcription. The authors hypothesized that MLX may be a key element of a transcription factor network, and that WBSCR14 may contribute to some aspects of the WBS pathology.
Billin et al. (2000) identified mouse Mondoa (608090) by yeast 2-hybrid analysis using human MLX as bait. Mouse Mondoa and Mlx associated in vivo, and the dimer localized primarily to the cytoplasm of mouse embryonic carcinoma cells. Treatment of cells with a nuclear export inhibitor resulted in nuclear accumulation of Mondoa and Mlx, demonstrating that the heterodimer shuttles between the cytoplasmic and nuclear compartments. The Mondoa-Mlx complex bound to the CACGTG E box in vitro and, when artificially targeted to the nucleus of mouse fibroblasts, drove reporter gene expression from the E box. Coexpression of MLX with truncation mutants of human MONDOA identified a transcription activation domain within the central STP-rich region of MONDOA. By mutation analysis, Billin et al. (2000) identified a cytoplasmic localization signal within the N terminus of human MONDOA that contributed to the cytoplasmic localization of the MONDOA-MLX complex.
Eilers et al. (2002) determined that 2 regions within the MONDOA N terminus contribute to the cytoplasmic localization of the MONDOA-MLX complex by functioning as a CRM1 (602559)-dependent nuclear export signal and as a binding site for 14-3-3 (see 601289) proteins, respectively. The conserved C terminus of MONDOA and MLX contains a cytoplasmic localization signal that directs cytoplasmic localization of the monomers and a protein-protein interaction domain that mediates interaction between MONDOA and MLX. Heterodimerization of MONDOA and MLX, via either the leucine zipper or the C-terminal domain, inactivates the C-terminal cytoplasmic localization signal. Inactivation of this domain is necessary but not sufficient for nuclear accumulation of the heterodimer.
Bjerknes and Cheng (1996) found that the TCFL4 gene has 8 exons and spans more than 5 kb.
Bjerknes and Cheng (1996) identified the TCFL4 gene in a human cosmid on chromosome 17q21.1, which also contains the HSD17B1 gene (109684).
Billin, A. N., Eilers, A. L., Coulter, K. L., Logan, J. S., Ayer, D. E. MondoA, a novel basic helix-loop-helix-leucine zipper transcriptional activator that constitutes a positive branch of a Max-like network. Molec. Cell. Biol. 20: 8845-8854, 2000. [PubMed: 11073985] [Full Text: https://doi.org/10.1128/MCB.20.23.8845-8854.2000]
Billin, A. N., Eilers, A. L., Queva, C., Ayer, D. E. Mlx, a novel Max-like BHLHZip protein that interacts with the Max network of transcription factors. J. Biol. Chem. 274: 36344-36350, 1999. [PubMed: 10593926] [Full Text: https://doi.org/10.1074/jbc.274.51.36344]
Bjerknes, M., Cheng, H. TCFL4: a gene at 17q21.1 encoding a putative basic helix-loop-helix leucine-zipper transcription factor. Gene 181: 7-11, 1996. [PubMed: 8973301] [Full Text: https://doi.org/10.1016/s0378-1119(96)00376-9]
Cairo, S., Merla, G., Urbinati, F., Ballabio, A., Reymond, A. WBSCR14, a gene mapping to the Williams-Beuren syndrome deleted region, is a new member of the Mlx transcription factor network. Hum. Molec. Genet. 10: 617-627, 2001. [PubMed: 11230181] [Full Text: https://doi.org/10.1093/hmg/10.6.617]
Eilers, A. L., Sundwall, E., Lin, M., Sullivan, A. A., Ayer, D. E. A novel heterodimerization domain, CRM1, and 14-3-3 control subcellular localization of the MondoA-Mlx heterocomplex. Molec. Cell. Biol. 22: 8514-8526, 2002. [PubMed: 12446771] [Full Text: https://doi.org/10.1128/MCB.22.24.8514-8526.2002]