Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 22, Issue 24, Pages 8514-8526Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.22.24.8514-8526.2002
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Funding
- NCI NIH HHS [P30 CA042014, 2P30 CA42014] Funding Source: Medline
- NIGMS NIH HHS [GM55668, R01 GM055668] Funding Source: Medline
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Among members of the bHLHZip family of transcriptional regulators, MondoA and Mix 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 Mix and a conserved domain in the N terminus of MondoA as important determinants of MondoA-Mlx subcellular localization. MondoA and Mix share sequence similarity in their bHLHZip domains and C termini. Here we show that for both MondoA and Mix, 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 Mix. Dimerization between MondoA and Mix inactivates the cytoplasmic localization activity of their C termini and is necessary for the heterocomplex to accumulate in the nucleus. MondoA-MIx 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-MIx by functioning as a CRMI-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 Mix 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.
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