Open AccessThe Multiple Endocrine Neoplasia Type 1 (MEN1) Tumor Suppressor Regulates Peroxisome Proliferator-Activated Receptor γ-Dependent Adipocyte Differentiation
Author(s) -
Koen M.A. Dreijerink,
Radhika A. Varier,
Olivier van Beekum,
Ellen H. Jeninga,
Jo W.M. Höppener,
Cornelis J.M. Lips,
J. Alain Kummer,
Eric Kalkhoven,
H. Th. Marc Timmers
Publication year - 2009
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.01001-08
Subject(s) - biology , men1 , peroxisome proliferator activated receptor , adipogenesis , transcription factor , cancer research , corepressor , microbiology and biotechnology , endocrinology , receptor , multiple endocrine neoplasia , nuclear receptor , gene , genetics , adipose tissue
Menin, the product of theMEN1 (m ultiplee ndocrinen eoplasia type1 ) 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 γ (PPARγ) is expressed in several MEN1-related tumor types, we investigated regulation of PPARγ activity by menin. We found that menin is required for adipocyte differentiation of murine 3T3-L1 cells and PPARγ-expressing mouse embryonic fibroblasts. Menin augments PPARγ target gene expression through recruitment of H3K4 methyltransferase activity. Menin interacts directly with the activation function 2 transcription activation domain of PPARγ in a ligand-independent fashion. Ligand-dependent coactivation, however, is dependent on the LXXLL motif of menin and the intact helix 12 of PPARγ. We propose that menin is an important factor in PPARγ-mediated adipogenesis and that loss of PPARγ function may contribute to lipoma development in MEN1 patients.