Ikaros modulates cholesterol uptake: A link between tumor suppression and differentiation
Ikaros modulates cholesterol uptake: A link between tumor suppression and differentiation
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DOI：
10.1158/0008-5472.can-08-0103
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发表时间：
2008-05-15
期刊：
影响因子：
11.2
通讯作者：
Ezzat, Shereen
中科院分区：
文献类型：
--
作者：
Loeper, Siobhan;Asa, Sylvia L.;Ezzat, Shereen
Ikaros是一种转录因子，指导淋巴细胞谱系承诺和垂体神经内分泌细胞的扩张和功能。在这里，我们发现Ikaros调节低密度脂蛋白受体（LDL-R）改变垂体代谢。corticotroph细胞。dna结合Ikaros亚型Ik1结合并增强LDL-R启动子的活性。Ik1降低LDL-R启动子上组蛋白H3的甲基化并增加其乙酰化（Lys(9)）。共聚焦显微镜和定量荧光测定显示，在ik1转染的细胞中，LDL内吞作用增强，表现出丰富的内质网、大的高尔基复合物和突出的分泌颗粒形成，与更强的胆固醇掺入功能相关的富膜细胞器一致。与这些数据一致的是，LDL-R-/-小鼠与Ik（-/-）小鼠一样，循环中促肾上腺皮质激素水平降低。这些发现扩大了Ikaros作用的范围，包括胆固醇摄取代谢途径的调节，对Ikaros相关癌症的脂质修饰药物的治疗意义。
Ikaros is a transcription factor that directs lymphoid lineage commitment and pituitary neuroendocrine cell expansion and function. Here, we show that Ikaros regulates the low-density lipoprotein receptor (LDL-R) to alter metabolism in pituitary. corticotroph cells. The DNA-binding Ikaros isoform Ik1 binds and enhances activity of the LDL-R promoter. Ik1 decreases methylation and increases acetylation of histone H3 (Lys(9)) at the LDL-R promoter. Confocal microscopy and quantitative fluorometry show enhanced LDL endocytosis in Ik1-transfected cells that exhibit abundant endoplasmic reticulum, large Golgi complexes, and prominent secretory granule formation, consistent with more robust cholesterol incorporation into functionally relevant membrane-rich organelles. Consistent with these data, LDL-R-/- mice, like Ik(-/-) mice, have decreased circulating levels of adrenocorticotropic hormone. These findings expand the repertoire of Ikaros actions to include regulation of the cholesterol uptake metabolic pathway with therapeutic implications for lipid-modifying drugs in Ikaros-associated cancers.