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Molecular and Cellular Biology, December 2002, p. 8514-8526, Vol. 22, No. 24
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.24.8514-8526.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

A Novel Heterodimerization Domain, CRM1, and 14-3-3 Control Subcellular Localization of the MondoA-Mlx Heterocomplex

Alanna L. Eilers, Eleanor Sundwall, Monica Lin, April A. Sullivan, and Donald E. Ayer^*

Huntsman Cancer Institute, Department of Oncological Sciences, University of Utah, Salt Lake City, Utah 84112-5550

Received 19 July 2002/ Returned for modification 4 September 2002/ Accepted 13 September 2002

Among members of the bHLHZip family of transcriptional regulators, MondoA and Mlx have the unique property of cytoplasmic localization. We have proposed that MondoA-Mlx heterodimers accumulate in the nucleus in response to extracellular cues. Our previous work implicated heterodimerization between MondoA and Mlx and a conserved domain in the N terminus of MondoA as important determinants of MondoA-Mlx subcellular localization. MondoA and Mlx share sequence similarity in their bHLHZip domains and C termini. Here we show that for both MondoA and Mlx, this C-terminal domain has cytoplasmic localization activity that is required by the protein monomers to accumulate in the cytoplasm. This C-terminal domain is also a novel dimerization interface that functions independently of the leucine zipper to mediate heterotypic interactions between MondoA and Mlx. Dimerization between MondoA and Mlx inactivates the cytoplasmic localization activity of their C termini and is necessary for the heterocomplex to accumulate in the nucleus. MondoA-Mlx heterodimers, while poised for nuclear entry, are retained in the cytoplasm by conserved domains in the N terminus of MondoA. Mondo conserved regions (MCRs) II and III contribute to cytoplasmic localization of MondoA-Mlx by functioning as a CRM1-dependent nuclear export signal and as a novel binding site for 14-3-3 family members, respectively. We propose that the nuclear accumulation of MondoA and Mlx is a two-step process. First, heterodimerization abolishes the cytoplasmic localization activity of their C termini. Second, an extracellular signal(s) must overcome the cytoplasmic localization function imparted by CRM1 and 14-3-3 binding to the N terminus of MondoA.

Present address: Pharmadigm, Inc., Salt Lake City, UT 84109-1405.

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