Critical role of PICT-1, a tumor suppressor candidate, in phosphatidylinositol 3,4,5-trisphosphate signals and tumorigenic transformation
Critical role of PICT-1, a tumor suppressor candidate, in phosphatidylinositol 3,4,5-trisphosphate signals and tumorigenic transformation
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DOI：
10.1091/mbc.e06-04-0301
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发表时间：
2006-11-01
影响因子：
3.3
通讯作者：
Maehama, Tomohiko
中科院分区：
文献类型：
--
作者：
Okahara, Fumiaki;Itoh, Kouichi;Maehama, Tomohiko
10号染色体上缺失的肿瘤抑制性磷酸酶和张力蛋白同源物（PTEN）通过使脂质第二信使磷脂酰肌醇3，4，5-三磷酸（PIP）去磷酸化来调节多种细胞功能。最近的研究表明，PICT-1/GLTSCR 2与细胞中的PTEN蛋白结合并稳定，暗示其在PTEN控制的PIP信号中的作用。在这项研究中，我们证明，RNA干扰介导的敲低HeLa细胞中的PICT-1下调内源性PTEN，并导致PIP，下游效应器，如蛋白激酶B/Akt的激活。此外，PICT-1敲低促进HeLa细胞增殖;然而，PTEN-null细胞的增殖不被PICT-1敲低改变，表明其依赖于PTEN状态。此外，星形孢菌素或血清耗竭诱导的HeLa细胞凋亡通过PICT-1敲低以类似的PTEN依赖性方式减轻。最引人注目的是，PICT-1在HeLa和NIH 3 T3细胞中的敲低促进了锚定非依赖性生长，这是致瘤转化的标志。此外，PICT-1在44例人神经母细胞瘤标本中的18例（41%）中异常表达，尽管存在PTEN mRNA，但PICT-1的缺失与PTEN蛋白表达减少相关。总之，这些结果表明PICT-1通过控制PTEN蛋白的稳定性在PIP信号中起作用，并且PICT-1-PTEN调节单元的损伤可能成为人类肿瘤的致病因素。
The tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) regulates diverse cellular functions by dephosphorylating the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate (PIP,). Recent study revealed that PICT-1/GLTSCR2 bound to and stabilized PTEN protein in cells, implicating its roles in PTEN-governed PIP, signals. In this study, we demonstrate that RNA interference-mediated knockdown of PICT-1 in HeLa cells down-regulated endogenous PTEN and resulted in the activation of PIP, downstream effectors, such as protein kinase B/Akt. Furthermore, the PICT-1 knockdown promoted HeLa cell proliferation; however the proliferation of PTEN-null cells was not altered by the PICT-1 knockdown, suggesting its dependency on PTEN status. In addition, apoptosis of HeLa cells induced by staurosporine or serum-depletion was alleviated by the PICT-1 knockdown in the similar PTEN-dependent manner. Most strikingly, the PICT-1 knockdown in HeLa and NIH3T3 cells promoted anchorage-independent growth, a hallmark of tumorigenic transformation. Furthermore, PICT-1 was aberrantly expressed in 18 (41%) of 44 human neuroblastoma specimens, and the PICT-1 loss was associated with reduced PTEN protein expression in spite of the existence of PTEN mRNA. Collectively, these results suggest that PICT-1 plays a role in PIP, signals through controlling PTEN protein stability and the impairment in the PICT-1-PTEN regulatory unit may become a causative factor in human tumor(s).