Protein phosphatase 2A and rapamycin regulate the nuclear localization and activity of the transcription factor GLI3
Protein phosphatase 2A and rapamycin regulate the nuclear localization and activity of the transcription factor GLI3
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DOI：
10.1158/0008-5472.can-07-6174
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发表时间：
2008-06-15
期刊：
影响因子：
11.2
通讯作者：
Schweiger, Susann
中科院分区：
文献类型：
--
作者：
Krauss, Sybille;Foerster, John;Schweiger, Susann
已经在广泛的肿瘤中发现了音刺猬（SHH）信号级联的功能获得性改变。三种SHH效应物GLI1、GLI2和GLI3调节参与细胞生长和细胞增殖的不同基因的转录。在这里，我们表明，蛋白磷酸酶2A（PP2A），其调节亚基，α 4，和雷帕霉素，雷帕霉素激酶复合物1（mTORC 1）的哺乳动物靶点的抑制剂，调节GLI3的核定位和转录活性。PP2A活性的增加或用雷帕霉素处理导致GLI3的胞质滞留，并因此减少GLI3靶基因和细胞周期调节因子细胞周期蛋白D1的转录。相反，PP2A的抑制导致细胞周期蛋白D1的表达增加。总之，我们的研究结果揭示了致癌SHH通路和肿瘤抑制因子PP2A之间存在迄今未被认识的分子串扰，并提出了雷帕霉素抗癌作用的新机制。
Gain-of-function alterations to the sonic hedgehog (SHH) signaling cascade have been found in a wide range of tumors. Three SHH effectors, GLI1, GLI2, and GLI3, regulate transcription of diverse genes involved in cell growth and cell proliferation. Here, we show that protein phosphatase 2A (PP2A), its regulatory subunit, alpha 4, and rapamycin, an inhibitor of the mammalian target of rapamycin kinase complex 1 (mTORC1), regulate the nuclear localization and transcriptional activity of GLI3. An increase in PP2A activity or treatment with rapamycin leads to cytosolic retention of GLI3 and, consequently, reduced transcription of the GLI3 target gene and cell cycle regulator, cyclin D1. Conversely, inhibition of PP2A results in increased expression of cyclin D1. In summary, our findings reveal the existence of a hitherto unrecognized molecular cross-talk between the oncogenic SHH pathway and the tumor suppressor PP2A and suggest a novel mechanism underlying the anticancerogenic effects of rapamycin.