Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, Israel.
PLoS One. 2010 May 27;5(5):e10859. doi: 10.1371/journal.pone.0010859.
The tumor suppressor PTEN (phosphatase and tensin homolog) is a lipid phosphatase that converts PIP3 into PIP2 and downregulates the kinase AKT and its proliferative and anti-apoptotic activities. The FoxO transcription factors are PTEN downstream effectors whose activity is negatively regulated by AKT-mediated phosphorylation. PTEN activity is frequently lost in many types of cancer, leading to increased cell survival and cell cycle progression.
Here we characterize the widely expressed miR-22 and report that miR-22 is a novel regulatory molecule in the PTEN/AKT pathway. miR-22 downregulates PTEN levels acting directly through a specific site on PTEN 3'UTR. Interestingly, miR-22 itself is upregulated by AKT, suggesting that miR-22 forms a feed-forward circuit in this pathway. Time-resolved live imaging of AKT-dependent FoxO1 phosphorylation revealed that miR-22 accelerated AKT activity upon growth factor stimulation, and attenuated its down regulation by serum withdrawal.
Our results suggest that miR-22 acts to fine-tune the dynamics of PTEN/AKT/FoxO1 pathway.
肿瘤抑制因子 PTEN（磷酸酶和张力蛋白同源物）是一种脂质磷酸酶，可将 PIP3 转化为 PIP2，并下调激酶 AKT 及其增殖和抗凋亡活性。FoxO 转录因子是 PTEN 的下游效应物，其活性受 AKT 介导的磷酸化负调控。PTEN 活性在许多类型的癌症中经常丢失，导致细胞存活增加和细胞周期进程。
在这里，我们描述了广泛表达的 miR-22，并报告 miR-22 是 PTEN/AKT 通路中的一种新型调节分子。miR-22 通过 PTEN 3'UTR 上的特定位点直接下调 PTEN 水平。有趣的是，miR-22 本身被 AKT 上调，这表明 miR-22 在该途径中形成了一个正反馈回路。AKT 依赖性 FoxO1 磷酸化的时分辨成像显示，miR-22 在生长因子刺激时加速 AKT 活性，并减弱了血清剥夺对其下调的作用。
我们的结果表明，miR-22 可精细调节 PTEN/AKT/FoxO1 通路的动态。
