The multiple endocrine neoplasia type 1 (MEN1) tumor suppressor regulates peroxisome proliferator-activated receptor gamma-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 (PPARgamma) is expressed in several MEN1-related tumor types, we investigated regulation of PPARgamma activity by menin. We found that menin is required for adipocyte differentiation of murine 3T3-L1 cells and PPARgamma-expressing mouse embryonic fibroblasts. Menin augments PPARgamma target gene expression through recruitment of H3K4 methyltransferase activity. Menin interacts directly with the activation function 2 transcription activation domain of PPARgamma in a ligand-independent fashion. Ligand-dependent coactivation, however, is dependent on the LXXLL motif of menin and the intact helix 12 of PPARgamma. We propose that menin is an important factor in PPARgamma-mediated adipogenesis and that loss of PPARgamma function may contribute to lipoma development in MEN1 patients.
Dreijerink
Koen M A
KM
University Medical Center Utrecht, Department of Physiological Chemistry, Utrecht, The Netherlands.
Varier
Radhika A
RA
van Beekum
Olivier
O
Jeninga
Ellen H
EH
Höppener
Jo W M
JW
Lips
Cornelis J M
CJ
Kummer
J Alain
JA
Kalkhoven
Eric
E
Timmers
H T Marc
HT
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology* / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation; D050556:Fatty Acid-Binding Proteins / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006657:Histones / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D051379:Mice; D047495:PPAR gamma / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D014158:Transcription, Genetic
C493410:FABP4 protein, human; D050556:Fatty Acid-Binding Proteins; D006657:Histones; D008024:Ligands; C105373:MEN1 protein, human; C484898:Men1 protein, mouse; D047495:PPAR gamma; D011518:Proto-Oncogene Proteins; D008239:Lysine