Mayo Marty W, Madrid Lee V, Westerheide Sandy D, Jones David R, Yuan Xiu-Juan, Baldwin Albert S, Whang Young E
Department of Biochemistry, University of Virginia, Charlottesville, Virginia 22908, USA.
J Biol Chem. 2002 Mar 29;277(13):11116-25. doi: 10.1074/jbc.M108670200. Epub 2002 Jan 17.
PTEN is a lipid phosphatase responsible for down-regulating the phosphoinositide 3-kinase product phosphatidylinositol 3,4,5-triphosphate. Phosphatidylinositol 3,4,5-triphosphate is involved in the activation of the anti-apoptotic effector target, Akt. Although the Akt pathway has been implicated in regulating NF-kappaB activity, it is controversial as to whether Akt activates NF-kappaB predominantly through mechanisms that regulate nuclear translocation or transactivation potential. In this report, we utilized PTEN as a natural biological inhibitor of Akt activity to study the effects on tumor necrosis factor (TNF)-induced activation of NF-kappaB. We found that the reintroduction of PTEN into prostate cells inhibited TNF-stimulated NF-kappaB transcriptional activity. PTEN failed to block TNF-induced IKK activation, IkappaBalpha degradation, p105 processing, p65 (RelA) nuclear translocation, and DNA binding of NF-kappaB. However, PTEN inhibited NF-kappaB-dependent transcription by blocking the ability of TNF to stimulate the transactivation domain of the p65 subunit. PTEN also inhibited the transactivation potential of the cyclic AMP-response element-binding protein, but this was not observed for c-Jun. The transactivation potential of p65 following TNF stimulation could be rescued from PTEN-dependent repression by re-introducing expression constructs encoding activated forms of phosphoinositide 3-kinase, Akt, or Akt and IKK. The ability of PTEN to inhibit the TNF-induced transactivation function of p65 is important, because expression of PTEN blocked TNF-stimulated NF-kappaB-dependent gene expression, thus sensitizing cells to TNF-induced apoptosis. Maintenance of the PTEN tumor suppressor protein is therefore required to modulate Akt activity and to concomitantly control the transcriptional activity of the anti-apoptotic transcription factor NF-kappaB.
PTEN是一种脂质磷酸酶，负责下调磷酸肌醇3激酶产物磷脂酰肌醇3,4,5 -三磷酸。磷脂酰肌醇3,4,5 -三磷酸参与抗凋亡效应靶点Akt的激活。尽管Akt信号通路与调节核因子κB（NF-κB）活性有关，但Akt是否主要通过调节核转位或反式激活潜能的机制来激活NF-κB仍存在争议。在本报告中，我们利用PTEN作为Akt活性的天然生物抑制剂，来研究其对肿瘤坏死因子（TNF）诱导的NF-κB激活的影响。我们发现，将PTEN重新导入前列腺细胞可抑制TNF刺激的NF-κB转录活性。PTEN未能阻断TNF诱导的IKK激活、IκBα降解、p105加工、p65（RelA）核转位以及NF-κB的DNA结合。然而，PTEN通过阻断TNF刺激p65亚基反式激活结构域的能力，抑制了NF-κB依赖的转录。PTEN还抑制了环磷酸腺苷反应元件结合蛋白的反式激活潜能，但c-Jun未出现这种情况。通过重新导入编码磷酸肌醇3激酶、Akt或Akt和IKK激活形式的表达构建体，可从PTEN依赖性抑制中挽救TNF刺激后p65的反式激活潜能。PTEN抑制TNF诱导的p65反式激活功能的能力很重要，因为PTEN的表达阻断了TNF刺激的NF-κB依赖基因表达，从而使细胞对TNF诱导的凋亡敏感。因此，需要维持PTEN肿瘤抑制蛋白来调节Akt活性，并同时控制抗凋亡转录因子NF-κB的转录活性。
