Menin is a tumor suppressor protein whose loss or inactivation causes multiple endocrine neoplasia type 1 (MEN1), a hereditary autosomal dominant tumor syndrome characterized by tumorigenesis in multiple endocrine organs1. Menin interacts with a multitude of proteins and involves in a variety of cellular processes2–6. Menin binds the Jun family transcription factor JunD and inhibits its transcriptional activity7,8. Several MEN1 missense mutations disrupted the menin-JunD interaction suggestive of a correlation between menin’s tumor suppressor function and its interaction with JunD and suppression of JunD activated transcription8,9. Menin also interacts with mixed lineage leukemia protein 1 MLL1, a histone H3 lysine 4 (H3K4) methyltransferase, and functions as an oncogenic cofactor to upregulate gene (including HOX genes) transcription and promote MLL1 fusion protein (MFP)-induced leukemogenesis10–12. A recent report on menin tethering MLL1 to chromatin binding factor LEDGF indicates menin as a molecular adaptor to coordinate the functions of multiple proteins13. Despite the importance of menin, it still remains poorly understood how menin could interact with many distinct partners and control multiple functions. Here we present the crystal structures of menin, free and in complexes with MLL1 or JunD, or an MLL1-LEDGF heterodimer. These structures show that menin contains a deep pocket that binds short peptides of MLL1 or JunD in the same manner, but oppositely regulates transcription. The menin-JunD interaction blocks JNK kinase-meidated JunD phosphorylation, a crucial event for JunD activation.Moreover, menin functions as a scaffold molecule to promote gene transcription by binding MLL1 through the peptide-pocket yet interacting with LEDGF at a distinct surface.

Background & Aims-Hedgehog signaling is critical in gastrointestinal patterning. Mice deficient in Hedgehog signaling exhibit abnormalities that mirror deformities seen in the human VACTERL (vertebral, anal, cardiac, tracheal, esophageal, renal, limb) association. However, the direction of Hedgehog signal flow is controversial and the cellular targets of Hedgehog signaling change with time during development. We profiled cellular Hedgehog response patterns from embryonic day 10.5 (E10.5) to adult in murine antrum, pyloric region, small intestine and colon.

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We have shown previously that a GC-rich element (GGGGCGGGGTGGGGGG) conferring epidermal growth factor (EGF) responsiveness to the human gastrin promoter binds Sp1 and additional undefined complexes. A rat GH4 cell line expression library was screened by using a multimer of the gastrin EGF response element, and three overlapping cDNA clones were identified. The full-length rat cDNA encoded an 89-kDa zinc finger protein (ZBP-89) that was 89% identical to a 49-kDa human factor, ht(beta), that binds a GTGGG/CACCC element in T-cell receptor promoters. The conservation of amino acids between the zinc fingers indicates that ZBP-89 is a member of the C2H2 zinc finger family subclass typified by the Drosophila Krüppel protein. ZBP-89 is ubiquitously expressed in normal adult tissues. It binds specifically to the gastrin EGF response element and inhibits EGF induction of the gastrin promoter. Collectively, these results demonstrate that ZBP-89 functions as a repressor of basal and inducible expression of the gastrin gene.