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Molecular and Cellular Biology, September 2009, p. 5060-5069, Vol. 29, No. 18
0270-7306/09/$08.00+0     doi:10.1128/MCB.01001-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

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

Koen M. A. Dreijerink,1,2,{dagger} Radhika A. Varier,1,{dagger} Olivier van Beekum,3 Ellen H. Jeninga,3 Jo W. M. Höppener,3 Cornelis J. M. Lips,2 J. Alain Kummer,4 Eric Kalkhoven,3,5 and H. T. Marc Timmers1*

Department of Physiological Chemistry,1 Department of Internal Medicine,2 Department of Metabolic and Endocrine Diseases,3 Department of Pathology,4 Department of Paediatric Immunology, University Medical Center Utrecht, Utrecht, The Netherlands5

Received 25 June 2008/ Returned for modification 18 August 2008/ Accepted 1 July 2009

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.

* Corresponding author. Mailing address: University Medical Center Utrecht, Department of Physiological Chemistry, STR 3.223, P.O. Box 85060, 3508 AB Utrecht, The Netherlands. Phone: 31 88 75 68989. Fax: 31 88 75 68101. E-mail: H.T.M.Timmers{at}umcutrecht.nl

{triangledown} Published ahead of print on 13 July 2009.

{dagger} K.M.A.D. and R.A.V. contributed equally to this work.

Molecular and Cellular Biology, September 2009, p. 5060-5069, Vol. 29, No. 18
0270-7306/09/$08.00+0     doi:10.1128/MCB.01001-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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