PTEN increases autophagy and inhibits the ubiquitin-proteasome pathway in glioma cells independently of its lipid phosphatase activity.
PTEN increases autophagy and inhibits the ubiquitin-proteasome pathway in glioma cells independently of its lipid phosphatase activity.
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DOI：
10.1371/journal.pone.0083318
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Knecht E
中科院分区：
文献类型：
--
作者：
Errafiy R;Aguado C;Ghislat G;Esteve JM;Gil A;Loutfi M;Knecht E
细胞内蛋白质降解的两种主要机制，自噬和泛素-蛋白酶体途径，在哺乳动物细胞中起作用。在胶质母细胞瘤中经常突变的PTEN是编码双重特异性磷酸酶的肿瘤抑制基因，所述磷酸酶拮抗磷脂酰肌醇3-激酶I类/AKT/mTOR途径，所述途径是自噬的关键调节剂。在这里，我们研究了U87 MG人脑胶质瘤细胞中PTEN在自噬和泛素-蛋白酶体途径调节中的作用，因为两者在功能上是相关的，并且与癌症进展相关。由于U87 MG神经胶质瘤细胞缺乏功能性PTEN，我们使用稳定的克隆表达，在四环素诱导系统（Tet-on）的控制下，野生型PTEN和它的两个突变体，G129 E-PTEN和C124 S-PTEN，这两个突变体分别缺乏脂质磷酸酶活性和脂质和蛋白磷酸酶活性的这种蛋白。U87 MG胶质瘤细胞中PTEN的表达降低蛋白酶体活性，也降低蛋白泛素化。相反，PTEN的表达增加了自噬通量和溶酶体质量。有趣的是，尽管PTEN通过其脂质磷酸酶活性负调节磷脂酰肌醇3-激酶I类/AKT/mTOR信号通路，但U87 MG细胞中的两种作用均不依赖于该活性。这些结果表明，一个新的mTOR独立的信号通路，通过该通路，PTEN可以在相反的方向上调节细胞内蛋白质降解的主要机制。
Two major mechanisms of intracellular protein degradation, autophagy and the ubiquitin-proteasome pathway, operate in mammalian cells. PTEN, which is frequently mutated in glioblastomas, is a tumor suppressor gene that encodes a dual specificity phosphatase that antagonizes the phosphatidylinositol 3-kinase class I/AKT/mTOR pathway, which is a key regulator of autophagy. Here, we investigated in U87MG human glioma cells the role of PTEN in the regulation of autophagy and the ubiquitin-proteasome pathway, because both are functionally linked and are relevant in cancer progression. Since U87MG glioma cells lack a functional PTEN, we used stable clones that express, under the control of a tetracycline-inducible system (Tet-on), wild-type PTEN and two of its mutants, G129E-PTEN and C124S-PTEN, which, respectively, lack the lipid phosphatase activity only and both the lipid and the protein phosphatase activities of this protein. Expression of PTEN in U87MG glioma cells decreased proteasome activity and also reduced protein ubiquitination. On the contrary, expression of PTEN increased the autophagic flux and the lysosomal mass. Interestingly, and although PTEN negatively regulates the phosphatidylinositol 3-kinase class I/AKT/mTOR signaling pathway by its lipid phosphatase activity, both effects in U87MG cells were independent of this activity. These results suggest a new mTOR-independent signaling pathway by which PTEN can regulate in opposite directions the main mechanisms of intracellular protein degradation.
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影响因子：
3.5
作者：
Aguado C;Sarkar S;Korolchuk VI;Criado O;Vernia S;Boya P;Sanz P;de Córdoba SR;Knecht E;Rubinsztein DC
通讯作者：
Rubinsztein DC
DOI：
10.1016/j.biocel.2013.02.007
发表时间：
2013-05-01
影响因子：
4
作者：
Fu, Lei-lei;Cheng, Yan;Liu, Bo
通讯作者：
Liu, Bo
影响因子：
8
作者：
Iwamaru, A.;Kondo, Y.;Kondo, S.
通讯作者：
Kondo, S.
影响因子：
4.1
作者：
Ahn, Younghee;Hwang, Chae Young;Lee, Cheolju
通讯作者：
Lee, Cheolju
影响因子：
4.1
作者：
Fuertes, G;De Llano, JJM;Knecht, E
通讯作者：
Knecht, E