Haploinsufficient and predominant expression of multiple endocrine neoplasia type 1 (MEN1)-related genes, MLL, p27Kip1 and p18Ink4C in endocrine organs.
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.
Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.
Ryo
R
Taguchi
Masanobu
M
Yamada
Kazuhiko
K
Horiguchi
Takuya
T
Tomaru
Atsushi
A
Ozawa
Nobuyuki
N
Shibusawa
Koshi
K
Hashimoto
Shuichi
S
Okada
Tetsurou
T
Satoh
Masatomo
M
Mori
D000311:Adrenal Glands / Q000378:metabolism; D000818:Animals; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D057895:Haploinsufficiency; D011495:Histone-Lysine N-Methyltransferase; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018761:Multiple Endocrine Neoplasia Type 1 / Q000235:genetics*; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D010902:Pituitary Gland / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D013737:Testis / Q000378:metabolism
C493961:Cdkn1b protein, mouse; D050763:Cyclin-Dependent Kinase Inhibitor p18; C484898:Men1 protein, mouse; D011518:Proto-Oncogene Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse