The Multiple Endocrine Neoplasia Type 1 (MEN1) Tumor Suppressor Regulates Peroxisome Proliferator-Activated Receptor γ-Dependent Adipocyte Differentiation
The Multiple Endocrine Neoplasia Type 1 (MEN1) Tumor Suppressor Regulates Peroxisome Proliferator-Activated Receptor γ-Dependent Adipocyte Differentiation
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DOI：
10.1128/mcb.01001-08
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发表时间：
2009-09-15
影响因子：
5.3
通讯作者：
Timmers, H. T. Marc
中科院分区：
文献类型：
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作者：
Dreijerink, Koen M. A.;Varier, Radhika A.;Timmers, H. T. Marc
Menin是MEN1（多发性内分泌肿瘤1型）肿瘤抑制基因的产物，作为MLL1（混合谱系白血病1）/MLL2 （KMT2A/B）蛋白复合物的一部分，参与基因转录的激活，该蛋白复合物具有组蛋白H3 （H3K4）赖氨酸4的甲基转移酶活性。由于MEN1患者经常发生脂肪瘤，并且PPAR γ在几种与MEN1相关的肿瘤类型中表达，因此我们研究了menin对PPAR γ活性的调节。我们发现menin是小鼠3T3-L1细胞和表达PPAR γ的小鼠胚胎成纤维细胞的脂肪细胞分化所必需的。Menin通过募集H3K4甲基转移酶活性来增强PPAR γ靶基因的表达。Menin以与配体无关的方式直接与PPAR γ的激活功能2转录激活域相互作用。然而，配体依赖性共激活依赖于menin的LXXLL基序和PPAR γ的完整螺旋12。我们认为menin是PPAR γ介导的脂肪形成的一个重要因素，PPAR γ功能的丧失可能导致MEN1患者脂肪瘤的发展。
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.