The Multiple Endocrine Neoplasia Type 1 (MEN1) Tumor Suppressor Regulates Peroxisome Proliferator-Activated Receptor γ-Dependent Adipocyte Differentiation

Menin, the product of the MEN1 (multiple endocrine neoplasia type 1) tumor suppressor gene, is involved in activation of gene transcription as part of an MLL1 (mixed-lineage leukemia 1)/MLL2 (KMT2A/B)containing protein complex which harbors methyltransferase activity for lysine 4 of histone H3 (H3K4). As MEN1 patients frequently develop lipomas and peroxisome proliferator-activated receptor gamma (PPAR gamma) is expressed in several MEN1-related tumor types, we investigated regulation of PPAR gamma activity by menin. We found that menin is required for adipocyte differentiation of murine 3T3-L1 cells and PPAR gamma-expressing mouse embryonic fibroblasts. Menin augments PPAR gamma target gene expression through recruitment of H3K4 methyltransferase activity. Menin interacts directly with the activation function 2 transcription activation domain of PPAR gamma in a ligand-independent fashion. Ligand-dependent coactivation, however, is dependent on the LXXLL motif of menin and the intact helix 12 of PPAR gamma. We propose that menin is an important factor in PPAR gamma-mediated adipogenesis and that loss of PPAR gamma function may contribute to lipoma development in MEN1 patients.