The multiple endocrine neoplasia type 1 (MEN1) tumor suppressor regulates peroxisome proliferator-activated receptor γ-dependent adipocyte differentiation

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. T.Marc Timmers

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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 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.

Original languageEnglish
Pages (from-to)5060-5069
Number of pages10
JournalMolecular and Cellular Biology
Volume29
Issue number18
DOIs
Publication statusPublished - 1 Sep 2009

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