CREB is a novel nuclear target of PTEN phosphatase.
CREB is a novel nuclear target of PTEN phosphatase.
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CREB 是 PTEN 磷酸酶的新型核靶标。
DOI：
10.1158/0008-5472.can-10-3399
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发表时间：
2011-04-15
期刊：
影响因子：
11.2
通讯作者：
Yin Y
中科院分区：
文献类型：
--
作者：
Gu T;Zhang Z;Wang J;Guo J;Shen WH;Yin Y
PTEN磷酸酶是一种有效的肿瘤抑制剂，调节多种细胞功能。在细胞质中，PTEN使其主要脂质底物磷脂酰肌醇3，4，5-三磷酸去磷酸化，以拮抗磷脂酰肌醇3-激酶（PI 3 K）/AKT信号传导途径。越来越明显的是，PTEN在细胞核中发挥作用，并可能在转录调控中发挥重要作用，但其核靶点仍然难以捉摸。在这份报告中，我们证明了转录因子环磷酸腺苷反应元件结合蛋白（CREB）是一个蛋白质的目标，PTEN磷酸酶和PTEN缺陷导致CREB磷酸化的PI 3 K/AKT通路的独立。使用共聚焦免疫荧光和相互免疫沉淀，我们进一步表明，PTEN与CREB共定位，并与CREB的物理相互作用。此外，我们使用在体外和体内实验，以显示PTEN可以去磷酸化CREB的磷酸酶依赖性的方式，这表明CREB是一个底物的PTEN核磷酸酶。Pten的缺失导致多种CREB转录靶标的RNA水平升高和细胞增殖增加，这可以通过不可磷酸化的CREB突变体或CREB敲低来逆转。这些数据揭示了CREB介导的基因转录和细胞生长的PTEN调节机制。因此，我们的研究表征PTEN作为一个核磷酸酶的转录因子，并确定CREB作为一个新的蛋白质靶点的PTEN磷酸酶，这有助于更好地了解PTEN在细胞核中的功能。
PTEN phosphatase is a potent tumor suppressor that regulates multiple cellular functions. In the cytoplasm, PTEN dephosphorylates its primary lipid substrate, phosphatidylinositol 3,4,5-trisphosphate, to antagonize the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway. It has also become increasingly evident that PTEN functions in the nucleus and may play an important part in transcription regulation, but its nuclear targets remain elusive. In this report, we demonstrate the transcription factor cyclic AMP response element-binding protein (CREB) is a protein target of PTEN phosphatase and that PTEN deficiency leads to CREB phosphorylation independent of the PI3K/AKT pathway. Using confocal immunofluorescence and reciprocal immunoprecipitation, we further show that PTEN colocalizes with CREB and physically interacts with CREB. Moreover, we use both in vitro and in vivo experiments to show PTEN can dephosphorylate CREB in a phosphatase-dependent manner, suggesting that CREB is a substrate of PTEN nuclear phosphatase. Loss of Pten results in an elevated RNA level of multiple CREB transcriptional targets and increased cell proliferation, which can be reversed by a nonphosphorylatable CREB mutant or knockdown of CREB. These data reveal a mechanism for PTEN modulation of CREB-mediated gene transcription and cell growth. Our study thus characterizes PTEN as a nuclear phophatase of a transcription factor and identifies CREB as a novel protein target of PTEN phosphatase, which contributes to better understanding of PTEN function in the nucleus.