Regulation of Akt(ser473) phosphorylation by choline kinase in breast carcinoma cells.
Regulation of Akt(ser473) phosphorylation by choline kinase in breast carcinoma cells.
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DOI：
10.1186/1476-4598-8-131
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发表时间：
2009-12-31
期刊：
影响因子：
37.3
通讯作者：
Downward J
中科院分区：
文献类型：
--
作者：
Chua BT;Gallego-Ortega D;Ramirez de Molina A;Ullrich A;Lacal JC;Downward J
丝氨酸/苏氨酸激酶PKB/Akt在细胞生长和增殖、代谢和细胞存活等多种细胞过程中发挥重要作用。Akt通路的各种成分如PTEN和pi3激酶（P110α）在人类癌症中的突变突出了Akt通路的重要性。在本文中，我们采用针对所有人类激酶的RNA干扰文库来筛选参与Akt活化调控的激酶，特别是丝氨酸473磷酸化。在这里，我们用人kinome siRNA文库转染MDA-MB 468乳腺细胞系，并使用Akt的phosphoserine 473特异性抗体检测Akt的活化。筛选结果显示，Akt（ser473）的磷酸化可受90多种激酶的调控。有趣的是，通过siRNA或小分子抑制剂抑制胆碱激酶活性可以严重降低Akt（ser473）的磷酸化，而不是thr308。我们在这里表明，胆碱激酶对Akt磷酸化的调控是pi3k无关的。此外，使用胆碱激酶抑制剂治疗的异种移植物肿瘤显示Akt（ser473）磷酸化有统计学意义的降低。重要的是，在小鼠模型中，磷酸化的减少与这些异种移植物肿瘤的消退有关。高胆碱激酶的表达和活性与肿瘤的发展和转移有关。胆碱激酶参与肿瘤形成的机制尚不完全清楚。根据我们的数据，我们提出胆碱激酶在调节Akt（ser473）磷酸化中起关键作用，从而促进细胞存活和增殖。
The serine/threonine kinase PKB/Akt plays essential role in various cellular processes including cell growth and proliferation, metabolism and cell survival. The importance of the Akt pathway is highlighted by the mutation of various components of the pathway such as the PTEN and PI3-kinase (P110α) in human cancers. In this paper, we employed an RNA interference library targeting all human kinases to screen for kinases involved in the regulation of Akt activation, in particular serine 473 phosphorylation. Here, we transfected the MDA-MB 468 breast cell line with the human kinome siRNA library and measured Akt activation using an antibody specific for phosphoserine 473 of Akt. The screen revealed that phosphorylation of Akt(ser473) can be regulated by more than 90 kinases. Interestingly, phosphorylation of Akt(ser473), but not thr308, can be severely reduced by inhibition of Choline kinase activity via siRNA or small molecule inhibitors. We show here that the regulation of Akt phosphorylation by Choline kinase is PI3K-independent. In addition, xenograft tumors treated with Choline kinase inhibitors demonstrated a statistically significant decrease in Akt(ser473) phosphorylation. Importantly, the reduction in phosphorylation correlates with regression of these xenograft tumors in the mouse model. High Choline kinase expression and activity has previously been implicated in tumor development and metastasis. The mechanism by which Choline kinase is involved in tumor formation is still not fully resolved. From our data, we proposed that Choline kinase plays a key role in regulating Akt(ser473) phosphorylation, thereby promoting cell survival and proliferation.
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DOI：
10.1016/s0006-291x(02)00920-8
发表时间：
2002-08-23
影响因子：
3.1
作者：
Ramírez de Molina, A;Rodríguez-González, A;Lacal, JC
通讯作者：
Lacal, JC
影响因子：
51.1
作者：
Ramirez de Molina, Ana;Sormentero-Estrada, Jacinto;Lacal, Juan Carlos
通讯作者：
Lacal, Juan Carlos
影响因子：
6.4
作者：
Eliyahu, Galit;Kreizman, Tamar;Degani, Hadassa
通讯作者：
Degani, Hadassa
影响因子：
2.9
作者：
NEGENDANK, W
通讯作者：
NEGENDANK, W
影响因子：
11.2
作者：
Al-Saffar, NMS;Troy, H;Chung, YL
通讯作者：
Chung, YL