Akt stimulates the transactivation potential of the RelA/p65 subunit of NF-κB through utilization of the IκB kinase and activation of the mitogen-activated protein kinase p38
Akt stimulates the transactivation potential of the RelA/p65 subunit of NF-κB through utilization of the IκB kinase and activation of the mitogen-activated protein kinase p38
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DOI：
10.1074/jbc.m101103200
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发表时间：
2001-06-01
影响因子：
4.8
通讯作者：
Baldwin, AS
中科院分区：
文献类型：
--
作者：
Madrid, LV;Mayo, MW;Baldwin, AS
丝氨酸/苏氨酸激酶Akt/PKB是一种有效的细胞存活调节因子，并具有致癌转化潜力。以前，已经表明Akt可以激活转录因子NF-κ B，并且这起到阻断由某些刺激诱导的细胞凋亡的作用。Akt激活NF-κ B的机制一直存在争议，有证据支持通过激活I κ B激酶活性和/或刺激NF-κ B的转录功能诱导NF-κ B的核转位。在这里，我们证明Akt通过刺激RelA/p65的反式激活结构域来靶向NF-κ B的反式激活功能，其方式依赖于I κ B激酶β活性和促分裂原活化蛋白激酶p38（p38）。RelA/ p65反式激活功能的激活需要丝氨酸529和536，这些位点先前显示为可诱导磷酸化的。与NF-κ B转录功能激活中p38的需要一致，激活的Akt的表达诱导p38活性。此外，已知IL-1 β激活NF-κ B的能力涉及Akt，我们在此表明IL-1 β以依赖于Akt和I κ B激酶激活的方式诱导p38活性。有趣的是，激活的Akt和转录共激活因子CBP/p300在RelA/p65反式激活结构域的激活中协同作用，并且这种协同作用被p38抑制剂阻断。这些研究表明，Akt通过I kappaB激酶和p38发挥作用，通过刺激NF-κ B的RelA/p65反式激活亚基来诱导NF-κ B的转录功能。
The serine/threonine kinase Akt/PKB is a potent regulator of cell survival and has oncogenic transformation potential. Previously, it has been shown that Akt can activate the transcription factor NF-kappaB and that this functions to block apoptosis induced by certain stimuli. The mechanism whereby Akt activates NF-kappaB has been controversial, with evidence supporting induction of nuclear translocation of NF-kappaB via activation of I kappaB kinase activity and/or the stimulation of the transcription function of NF-kappaB. Here we demonstrate that Akt targets the transactivation function of NF-kappaB by stimulating the transactivation domain of RelA/p65 in a manner that is dependent on I kappaB kinase beta activity and on the mitogen-activated protein kinase p38 (p38), Activation of RelA/ p65 transactivation function requires serines 529 and 536, sites shown previously to be inducibly phosphorylated. Consistent with the requirement of p38 in the activation of NF-kappaB transcriptional function, expression of activated Akt induces p38 activity. Furthermore, the ability of IL-I beta to activate NF-kappaB is known to involve Akt, and we show here that IL-1 beta induces p38 activity in manner dependent on Akt and I kappaB kinase activation. Interestingly, activated Akt and the transcriptional coactivators CBP/p300 synergize in the activation of the RelA/p65 transactivation domain, and this synergy is blocked by p38 inhibitors. These studies demonstrate that Akt, functioning through I kappaB kinase and p38, induces the transcription function of NF-kappaB by stimulating the RelA/p65 transactivation subunit of NF-kappaB.