A novel PTEN-dependent link to ubiquitination controls FLIPS stability and TRAIL sensitivity in glioblastoma multiforme.
A novel PTEN-dependent link to ubiquitination controls FLIPS stability and TRAIL sensitivity in glioblastoma multiforme.
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DOI：
10.1158/0008-5472.can-09-1287
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发表时间：
2009-10-15
期刊：
影响因子：
11.2
通讯作者：
Pieper RO
中科院分区：
文献类型：
--
作者：
Panner A;Crane CA;Weng C;Feletti A;Parsa AT;Pieper RO
多形性胶质母细胞瘤（GBM）中，akt -哺乳动物雷帕霉素靶蛋白（mTOR）通路的磷酸酶和紧张素同源物（PTEN）丢失和激活可增加mRNA翻译，增加抗凋亡蛋白FLIPS的水平，并对肿瘤坏死因子相关凋亡诱导配体（TRAIL）诱导的凋亡产生抵抗。然而，在PTEN缺失的GBM细胞中，FLIPS蛋白也表现出比PTEN突变的GBM细胞更长的半衰期，而这种更长的半衰期与FLIPS多泛素化降低有关。暴露于Akt抑制剂而非雷帕霉素下，PTEN突变体GBM细胞中的FLIPS半衰期缩短，这表明PTEN与泛素依赖性蛋白稳定性控制之间存在先前描述的mtor无关的联系。候选FLIPS E3泛素连接酶萎缩蛋白相互作用蛋白4 （AIP4）的总水平在PTEN野生型（WT）和PTEN突变型GBM细胞中是相当的，尽管在PTEN缺陷细胞中，AIP4维持在稳定的多泛素化状态，与FLIPS或含有FLIPS的死亡诱导信号复合物的关联能力较弱。小干扰rna介导的PTEN WT细胞中AIP4水平的抑制降低了FLIPS的泛素化，延长了FLIPS的半衰期，增加了TRAIL抗性。同样，Akt激活之前被证明会增加TRAIL抗性，但不会改变AIP4水平，但会增加AIP4泛素化，增加FLIPS稳态水平，并抑制FLIPS泛素化。这些结果确定了PTEN- akt - aip4通路是FLIPS泛素化、FLIPS稳定性和TRAIL敏感性的关键调节因子，并确定了PTEN与泛素介导的蛋白质稳定性控制之间的新联系。
Phosphatase and tensin homologue (PTEN) loss and activation of the Akt-mammalian target of rapamycin (mTOR) pathway increases mRNA translation, increases levels of the antiapoptotic protein FLIPS, and confers resistance to tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)–induced apoptosis in glioblastoma multiforme (GBM). In PTEN-deficient GBM cells, however, the FLIPS protein also exhibited a longer half-life than in PTEN mutant GBM cells, and this longer half-life correlated with decreased FLIPS polyubiquitination. FLIPS half-life in PTEN mutant GBM cells was reduced by exposure to an Akt inhibitor, but not to rapamycin, suggesting the existence of a previously undescribed, mTOR-independent linkage between PTEN and the ubiquitin-dependent control of protein stability. Total levels of the candidate FLIPS E3 ubiquitin ligase atrophin-interacting protein 4 (AIP4) were comparable in PTEN wild-type (WT) and PTEN mutant GBM cells, although in PTEN-deficient cells, AIP4 was maintained in a stable polyubiquitinated state that was less able to associate with FLIPS or with the FLIPS-containing death inducing signal complex. Small interfering RNA–mediated suppression of AIP4 levels in PTEN WT cells decreased FLIPS ubiquitination, prolonged FLIPS half-life, and increased TRAIL resistance. Similarly, the Akt activation that was previously shown to increase TRAIL resistance did not alter AIP4 levels, but increased AIP4 ubiquitination, increased FLIPS steady-state levels, and suppressed FLIPS ubiquitination. These results define the PTEN-Akt-AIP4 pathway as a key regulator of FLIPS ubiquitination, FLIPS stability, and TRAIL sensitivity and also define a novel link between PTEN and the ubiquitin-mediated control of protein stability.