Schneider L, Essmann F, Kletke A, Rio P, Hanenberg H, Schulze-Osthoff K, Nürnberg B, Piekorz R P
Institut für Biochemie und Molekularbiologie II, Universitätsklinikum der Heinrich-Heine-Universität, Düsseldorf, Germany.
Oncogene. 2008 Jan 3;27(1):116-25. doi: 10.1038/sj.onc.1210628. Epub 2007 Jun 25.
Regulators of the mitotic spindle apparatus are attractive cellular targets for antitumor therapy. The centrosomal protein transforming acidic coiled coil (TACC) 3 is required for spindle assembly and proper chromosome segregation. In this study, we employed an inducible RNA interference approach to downregulate TACC3 expression. We show that TACC3 knock-down in NIH3T3 fibroblasts caused aneuploidy, but failed to overtly impair mitotic progression. TACC3 depletion rather triggered a postmitotic p53-p21(WAF) pathway and led to a reversible cell cycle arrest. Similar effects were induced by low concentrations of paclitaxel, a spindle poison used in antitumor therapy. Interestingly, however, and unlike in TACC3-proficient cells, paclitaxel was able to induce strong polyploidy and subsequent apoptosis in TACC3-depleted cells. Even though paclitaxel treatment was associated with the activation of the survival kinase Akt and an antiapoptotic expression of cytoplasmic p21(WAF) and cyclin D1, this inhibition of cell death was abrogated by depletion of TACC3. Thus, our data identify TACC3 as a potential target to overcome p21(WAF)-associated protection of transformed cells against paclitaxel-induced cell death.
有丝分裂纺锤体装置的调节因子是抗肿瘤治疗中具有吸引力的细胞靶点。中心体蛋白转化酸性卷曲螺旋（TACC）3是纺锤体组装和正确染色体分离所必需的。在本研究中，我们采用诱导性RNA干扰方法下调TACC3的表达。我们发现，NIH3T3成纤维细胞中TACC3基因敲低会导致非整倍体，但并未明显损害有丝分裂进程。TACC3缺失反而触发了有丝分裂后p53-p21（WAF）通路，并导致可逆的细胞周期停滞。低浓度的紫杉醇（一种用于抗肿瘤治疗的纺锤体毒素）也能诱导类似的效应。然而，有趣的是，与TACC3正常的细胞不同，紫杉醇能够在TACC3缺失的细胞中诱导强烈的多倍体形成及随后的凋亡。尽管紫杉醇治疗与存活激酶Akt的激活以及细胞质p21（WAF）和细胞周期蛋白D1的抗凋亡表达有关，但TACC3的缺失消除了这种对细胞死亡的抑制作用。因此，我们的数据表明TACC3是克服p21（WAF）相关的转化细胞对紫杉醇诱导的细胞死亡保护作用的潜在靶点。
