Transcriptional Activation of the Mixed Lineage Leukemia–p27Kip1 Pathway by a Somatostatin Analogue
Transcriptional Activation of the Mixed Lineage Leukemia–p27Kip1 Pathway by a Somatostatin Analogue
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DOI：
10.1158/1078-0432.ccr-08-2473
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发表时间：
2009-04
影响因子：
11.5
通讯作者：
Kazuhiko Horiguchi;M. Yamada;T. Satoh;K. Hashimoto;J. Hirato;M. Tosaka;S. Yamada;M. Mori
中科院分区：
文献类型：
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作者：
Kazuhiko Horiguchi;M. Yamada;T. Satoh;K. Hashimoto;J. Hirato;M. Tosaka;S. Yamada;M. Mori
目的：混合细胞性白血病(MLL)是一种组蛋白甲基转移酶，能激活基因转录，并与脑膜素相关。在多发性内分泌肿瘤1型(MEN1)中，脑膜素突变导致p27Kip1和p18Ink4C基因表达降低，细胞生长紊乱。我们推测，散发性垂体腺瘤可能也涉及同样的途径。实验设计：检测了几个散发性垂体腺瘤标本中MLL、MEN1、p27Kip1和p18Ink4C的mRNA水平，临床参数搜索显示奥曲肽治疗影响了所测试的一些基因的表达水平。为了研究分子机制，我们克隆和鉴定了MLL启动子区域，并使用小干扰RNA来处理MLL，并使用特异性抑制剂来进行信号转导。结果：在催乳素瘤和生长激素分泌腺瘤中，MLL和p27Kip1的mRNA水平有很强的相关性，除了生长激素分泌腺瘤用生长抑素类似物奥曲肽治疗外，这些水平都有所减弱。相反，接受奥曲肽治疗的患者显示出高水平的MLL-p27Kip1mRNA。体外实验表明，奥曲肽可增加MLL和p27Kip1的蛋白和mRNA水平，并且过表达MLL可显著提高p27Kip1启动子的活性。此外，奥曲肽通过磷脂酰肌醇3-激酶/Akt和丝裂原活化蛋白激酶途径激活MLL基因的启动子活性。此外，与甲基转移酶抑制剂MTA孵育和敲除MLL完全抑制了奥曲肽诱导的p27Kip1的表达。结论：MLL-p27Kip1途径在垂体腺瘤中下调，奥曲肽通过磷脂酰肌醇3-激酶/Akt和丝裂原活化蛋白激酶途径顺序转录刺激MLL和p27Kip1基因，至少部分提高了p27Kip1水平。
Purpose: Mixed lineage leukemia (MLL) is a histone methyltransferase that activates gene transcription and associates with menin. In multiple endocrine neoplasia type 1 (Men1), a mutation of menin caused decreased expression of the p27Kip1 and p18Ink4C genes and deregulated cell growth. We hypothesized that the same pathway might be involved in sporadic pituitary adenomas. Experimental Design: mRNA levels for MLL, Men1, p27Kip1, and p18Ink4C were measured in specimens of several sporadic pituitary adenomas, and a search for clinical parameters revealed that octreotide treatment affected the level of expression of some genes tested. To study molecular mechanisms, we cloned and characterized the MLL promoter region and used small interfering RNA for MLL and specific inhibitors for signal transduction pathways. Results: A strong correlation between MLL and p27Kip1 mRNA levels was observed in prolactinomas and growth hormone–secreting adenomas, and these levels were attenuated except in growth hormone–secreting adenomas treated with a somatostatin analogue, octreotide. Conversely, the patients treated with octreotide showed high levels of MLL-p27Kip1 mRNA. Experiments in vitro showed that octreotide increased MLL and p27Kip1 protein and mRNA levels, and overexpression of MLL induced a marked increase in p27Kip1promoter activity. Furthermore, octreotide stimulated the promoter activity of the MLL gene through phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase pathways. In addition, incubation with an inhibitor for methyltransferase, MTA, and knockdown of MLL completely inhibited the octreotide-induced expression of p27Kip1. Conclusions: The MLL-p27Kip1 pathway was down-regulated in the pituitary adenomas, and octreotide increased the p27Kip1 level, at least in part, by sequential transcriptional stimulation of the MLL and p27Kip1 genes through phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase pathways.