DAB2IP coordinates both PI3K-Akt and ASK1 pathways for cell survival and apoptosis
DAB2IP coordinates both PI3K-Akt and ASK1 pathways for cell survival and apoptosis
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DOI：
10.1073/pnas.0908458106
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发表时间：
2009-11-24
影响因子：
11.1
通讯作者：
Hsieh, Jer-Tsong
中科院分区：
文献类型：
--
作者：
Xie, Daxing;Gore, Crystal;Hsieh, Jer-Tsong
在转移性前列腺癌（PCa）细胞中，经常检测到细胞存活和死亡信号之间的不平衡，例如磷脂酰肌醇3-激酶（PI 3 K）-Akt的组成性激活和凋亡刺激激酶（ASK 1）-JNK途径的失活。在这里，我们发现，DAB 2 IP蛋白，通常下调PCa，是一个有效的生长抑制剂，诱导G（0）/G（1）细胞周期停滞，并在应激反应中促凋亡。功能获得研究表明，DAB 2 IP可以抑制PI 3 K-Akt通路并增强ASK 1活化，导致细胞凋亡，而DAB 2 IP表达的缺失导致PI 3 K-Akt活化和ASK 1-JNK失活，导致体内PCa生长加速。此外，来自DAB 2 IP（-/-）动物的腺上皮细胞表现出增生和凋亡缺陷。DAB 2 IP蛋白的结构功能分析表明，除了C2结构域在ASK 1活性中的关键作用外，富含脯氨酸（PR）和PERIOD-like（PER）结构域对调节PI 3 K-Akt活性也很重要。因此，DAB 2 IP是一种能够桥接存活和死亡信号分子的支架蛋白，这意味着它在维持细胞稳态中的作用。
In metastatic prostate cancer (PCa) cells, imbalance between cell survival and death signals such as constitutive activation of phosphatidylinositol 3-kinase (PI3K)-Akt and inactivation of apoptosis-stimulated kinase (ASK1)-JNK pathways is often detected. Here, we show that DAB2IP protein, often down-regulated in PCa, is a potent growth inhibitor by inducing G(0)/G(1) cell cycle arrest and is proapoptotic in response to stress. Gain of function study showed that DAB2IP can suppress the PI3K-Akt pathway and enhance ASK1 activation leading to cell apoptosis, whereas loss of DAB2IP expression resulted in PI3K-Akt activation and ASK1-JNK inactivation leading to accelerated PCa growth in vivo. Moreover, glandular epithelia from DAB2IP(-/-) animal exhibited hyperplasia and apoptotic defect. Structural functional analyses of DAB2IP protein indicate that both proline-rich (PR) and PERIOD-like (PER) domains, in addition to the critical role of C2 domain in ASK1 activity, are important for modulating PI3K-Akt activity. Thus, DAB2IP is a scaffold protein capable of bridging both survival and death signal molecules, which implies its role in maintaining cell homeostasis.