Akt-mediated regulation of NFkappaB and the essentialness of NFkappaB for the oncogenicity of PI3K and Akt.
Akt-mediated regulation of NFkappaB and the essentialness of NFkappaB for the oncogenicity of PI3K and Akt.
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DOI：
10.1002/ijc.24748
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发表时间：
2009-12-15
影响因子：
6.4
通讯作者：
Vogt, Peter K.
中科院分区：
文献类型：
--
作者：
Bai, Dong;Ueno, Lynn;Vogt, Peter K.
丝氨酸/苏氨酸激酶Akt(小鼠胸腺瘤病毒akt8癌基因的细胞同源基因)，也被称为蛋白激酶B(Protein Kinase B)，由磷脂酰肌醇3-激酶(PI3K)的脂产物激活。AKT磷酸化了许多控制细胞存活、增殖和运动的蛋白质靶点。以往的研究表明，Akt通过诱导核转录因子-κB(NF-κB)的磷酸化和随后的κB抑制物(IκB)的降解来调节其转录活性。我们发现，在肉豆蔻化κ(MyrAkt)转化的鸡胚胎成纤维细胞(CEF)中，核因子MyrAkt B驱动的转录增加。因此，AKT和AKT抑制剂的显性负突变都抑制了NFκB依赖的转录。在AKT转化的细胞中，IκB蛋白的降解被强烈地促进，而通过引入NFκB的超级抑制子IκBSR而导致的NFκB活性的丧失干扰了PI3K和AKT诱导的CEF的致癌转化。在AKT转化的细胞中，丝氨酸534位的NFκB的p65亚单位的磷酸化也上调。我们的结果表明，AKT对NFκB的刺激依赖于S534上p65的磷酸化，这种磷酸化依赖于IKK(IκB Kinase)α和β。Akt使T23上的ikkα磷酸化，这一磷酸化事件是IKKα和β在S534处磷酸化p65的先决条件。我们的结果表明，在具有结构性κ活性的细胞中，IKK复合体在NFκB的激活中具有两个独立的功能：I Akt B的磷酸化和随后的降解以及p65的磷酸化。这些数据进一步支持了NFκB活性在PI3K和AKT诱导的致癌转化中所必需的这一结论。
The serine/threonine kinase Akt (cellular homolog of murine thymoma virus akt8 oncogene), also known as PKB (protein kinase B), is activated by lipid products of phosphatidylinositol 3-kinase (PI3K). Akt phosphorylates numerous protein targets that control cell survival, proliferation and motility. Previous studies suggest that Akt regulates transcriptional activity of the nuclear factor-κB (NFκB) by inducing phosphorylation and subsequent degradation of inhibitor of κB (IκB). We show here that NFκB-driven transcription increases in chicken embryonic fibroblasts (CEF) transformed by myristylated Akt (myrAkt). Accordingly, both a dominant negative mutant of Akt and Akt inhibitors repress NFκB-dependent transcription. The degradation of the IκB protein is strongly enhanced in Akt-transformed cells, and the loss of NFκB activity by introduction of a super-repressor of NFκB, IκBSR, interferes with PI3K- and Akt-induced oncogenic transformation of CEF. The phosphorylation of the p65 subunit of NFκB at serine 534 is also upregulated in Akt-transformed cells. Our data suggest that the stimulation of NFκB by Akt is dependent on the phosphorylation of p65 at S534, mediated by IKK (IκB kinase) α and β. Akt phosphorylates IKKα on T23, and this phosphorylation event is a prerequisite for the phosphorylation of p65 at S534 by IKKα and β. Our results demonstrate two separate functions of the IKK complex in NFκB activation in cells with constitutive Akt activity: the phosphorylation and consequent degradation of IκB and the phosphorylation of p65. The data further support the conclusion that NFκB activity is essential for PI3K- and Akt-induced oncogenic transformation.
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影响因子：
64.8
作者：
Lawrence, T;Bebien, M;Karin, M
通讯作者：
Karin, M
影响因子：
4.8
作者：
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影响因子：
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作者：
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作者：
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Baldwin, AS
DOI：
10.1073/pnas.95.25.14950
发表时间：
1998-12-08
影响因子：
11.1
作者：
Aoki, M;Batista, O;Vogt, PK
通讯作者：
Vogt, PK