microRNA-451 A conditional switch controlling glioma cell proliferation and migration
microRNA-451 A conditional switch controlling glioma cell proliferation and migration
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DOI：
10.4161/cc.9.14.12248
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发表时间：
2010-07-15
期刊：
影响因子：
4.3
通讯作者：
Lawler, Sean
中科院分区：
文献类型：
--
作者：
Godlewski, Jakub;Bronisz, Agnieszka;Lawler, Sean
胶质母细胞瘤是最常见和最具侵袭性的原发脑肿瘤，生长迅速，浸润性强。对这些肿瘤的分子生物学、遗传学、病因和细胞起源的不完全了解可能会限制改进的治疗方法的发展。近年来，一个主要的和根本性的进展是鉴定了microRNAs是高度保守的基因表达调节因子。在这里，我们将进一步讨论我们最近发表的关于miR-451在胶质母细胞瘤生物学中的作用的数据。我们最初发现miR-451是因为它在胶质瘤细胞迁移实验中下调。我们随后发现，通过靶向LKB1激酶复合体，miR-451抑制了下游蛋白激酶的活性，包括主要的能量生物传感器AMPK。MiR-451水平受葡萄糖调节；在能量充足的条件下，miR-451高表达，AMPK信号的抑制使细胞通过不受抑制的mTOR激活来维持较高的增殖率。在停糖条件下，miR-451的下调是AMPK途径激活所必需的，从而抑制细胞的增殖速度，增加细胞的存活和迁移。我们还在LKB1和miR-451之间发现了一个潜在的反馈环，它允许对葡萄糖剥夺做出持续和强大的反应。这些数据将在潜在的生物学意义和治疗意义的背景下进行讨论。
Glioblastoma, the most common and aggressive primary brain tumor, is rapidly growing and highly infiltrative. Incomplete knowledge of the molecular biology, genetics, causes and cellular origin of these tumors may limit the development of improved therapeutics. A major and fundamental advance in recent years has been the identification of microRNAs as highly conserved regulators of gene expression. Here we will discuss further our recently published data on the role of miR-451 in the biology of glioblastoma. We initially identified miR-451 due to its downregulation in a glioma cell migration assay. We then found that by targeting the LKB1 kinase complex miR-451 suppresses the activity of downstream protein kinases including the major energy biosensor AMPK. MiR-451 levels are regulated by glucose; under conditions of abundant energy miR-451 expression is high, and the suppression of AMPK signaling allows cells to maintain elevated proliferation rates via unrestrained mTOR activation. Under conditions of glucose withdrawal, miR-451 downregulation is necessary for AMPK pathway activation, leading to suppressed proliferation rates, increased cell survival and migration. We also identified a potential feedback loop between LKB1 and miR-451, which allows a sustained and robust response to glucose deprivation. This data will be discussed in the context of potential biological significance and therapeutic implications.