Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.
Biochem Biophys Res Commun. 2011 Nov 18;415(2):378-83. doi: 10.1016/j.bbrc.2011.10.077. Epub 2011 Oct 21.
Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominantly inherited syndrome characterized by parathyroid, gastro-entero-pancreatic and anterior pituitary tumors. Although the tissue selectivity of tumors in specific endocrine organs is the very essence of MEN1, the mechanisms underlying the tissue-selectivity of tumors remain unknown. The product of the Men1 gene, menin, and mixed lineage leukemia (MLL) have been found to cooperatively regulate p27(Kip1)/CDKN1B (p27) and p18(Ink4C)/CDKN2C (p18) genes. However, there are no reports on the tissue distribution of these MEN1-related genes. We investigated the expression of these genes in the endocrine and non-endocrine organs of wild-type, Men1 knockout and MLL knockout mice. Men1 mRNA was expressed at a similar level in endocrine and non-endocrine organs. However, MLL, p27 and p18 mRNAs were predominantly expressed in the endocrine organs. Notably, p27 and MLL mRNAs were expressed in the pituitary gland at levels approximately 12- and 17-fold higher than those in the liver. The heterozygotes of Men1 knockout mice the levels of MLL, p27 and p18 mRNAs did not differ from those in the wild-type mice. In contrast, heterozygotes of MLL knockout mice showed significant reductions in p27 mRNA as well as protein levels in the pituitary and p27 and p18 in the pancreatic islets, but not in the liver. This study demonstrated for the first time the predominant expression MEN1-related genes, particularly MLL and p27, in the endocrine organs, and a tissue-specific haploinsuffiency of MLL, but not menin, may lead to a decrease in levels of p27 and p18 mRNAs in endocrine organs. These findings may provide basic information for understanding the mechanisms of tissue selectivity of the tumorigenesis in patients with MEN1.
多发性内分泌腺瘤病 1 型（MEN1）是一种罕见的常染色体显性遗传综合征，其特征为甲状旁腺、胃肠胰和垂体前叶肿瘤。尽管特定内分泌器官肿瘤的组织选择性是 MEN1 的本质特征，但肿瘤组织选择性的机制尚不清楚。Men1 基因的产物 menin 和混合谱系白血病（MLL）已被发现协同调节 p27（Kip1）/CDKN1B（p27）和 p18（Ink4C）/CDKN2C（p18）基因。然而，目前尚无关于这些与 MEN1 相关基因的组织分布的报道。我们研究了这些基因在野生型、Men1 敲除和 MLL 敲除小鼠的内分泌和非内分泌器官中的表达情况。Men1 mRNA 在内分泌和非内分泌器官中的表达水平相似。然而，MLL、p27 和 p18 mRNA 主要在内分泌器官中表达。值得注意的是，p27 和 MLL mRNA 在垂体中的表达水平比在肝脏中高约 12 倍和 17 倍。Men1 敲除杂合子小鼠的 MLL、p27 和 p18 mRNA 水平与野生型小鼠无差异。相比之下，MLL 敲除杂合子小鼠的 p27 mRNA 及其在垂体和胰腺胰岛中的蛋白水平显著降低，但在肝脏中则无此现象。本研究首次证明 MEN1 相关基因，特别是 MLL 和 p27，在内分泌器官中表达占优势，MLL 而非 menin 的组织特异性杂合不足可能导致内分泌器官中 p27 和 p18 mRNA 水平降低。这些发现可能为理解 MEN1 患者肿瘤发生的组织选择性机制提供基础信息。
