Gao Ping, Wange Ronald L, Zhang Ning, Oppenheim Joost J, Howard O M Zack
Laboratory of Molecular Immunoregulation, Center for Cancer Research, National Cancer Institute-Frederick, PO Box B, Bldg 560, Rm 31-19, Frederick, MD 21702-1201, USA.
Blood. 2005 Oct 15;106(8):2619-26. doi: 10.1182/blood-2004-08-3362. Epub 2005 Jun 30.
Phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a multifunctional tumor suppressor, has been shown to play a regulatory role in cell migration. Dictyostelium discoideum cells lacking PTEN exhibited impaired migration toward chemoattractant gradients. In the present study, we investigated the involvement of PTEN in chemotaxis of mammalian cells by examining PTEN-null Jurkat T cells. We observed that, in contrast to observations made in D discoideum, PTEN-null Jurkat T cells exhibited potent chemotactic responses to the chemokine stromal cell-derived factor 1alpha (SDF-1alpha), indicating that PTEN was not requisite for CXC chemokine receptor 4 (CXCR4)-mediated chemotaxis of Jurkat cells. Conversely, reconstitution of PTEN in Jurkat cells by using a tetracycline (Tet-on)-inducible expression system down-regulated CXCR4-mediated chemotaxis. Furthermore, we established the lipid phosphatase activity of PTEN as essential for its inhibitory effect on chemotaxis. In addition, using PTEN-expressing T-cell lines and primary T cells, we demonstrated that down-regulation of PTEN expression with vector-based small interfering RNAs (siRNAs) enhanced CXCR4-mediated chemotaxis. Based on these results, we conclude that PTEN expression negatively regulates chemotaxis of lymphoid mammalian cells via its lipid phosphatase activity. Our findings may account for the reported increase in metastatic activity of PTEN-null tumor cells.
10号染色体缺失的磷酸酶及张力蛋白同源物（PTEN）是一种多功能肿瘤抑制因子，已被证明在细胞迁移中发挥调节作用。缺乏PTEN的盘基网柄菌细胞向趋化因子梯度的迁移受损。在本研究中，我们通过检测PTEN基因敲除的Jurkat T细胞，研究了PTEN在哺乳动物细胞趋化作用中的作用。我们观察到，与在盘基网柄菌中的观察结果相反，PTEN基因敲除的Jurkat T细胞对趋化因子基质细胞衍生因子1α（SDF-1α）表现出强烈的趋化反应，这表明PTEN对于Jurkat细胞中CXC趋化因子受体4（CXCR4）介导的趋化作用不是必需的。相反，通过使用四环素（Tet-on）诱导表达系统在Jurkat细胞中重建PTEN会下调CXCR4介导的趋化作用。此外，我们确定PTEN的脂质磷酸酶活性对其趋化抑制作用至关重要。另外，使用表达PTEN的T细胞系和原代T细胞，我们证明基于载体的小干扰RNA（siRNA）下调PTEN表达可增强CXCR4介导的趋化作用。基于这些结果，我们得出结论，PTEN表达通过其脂质磷酸酶活性对淋巴样哺乳动物细胞的趋化作用产生负调节。我们的发现可能解释了报道的PTEN基因敲除肿瘤细胞转移活性增加的现象。
