Tpx2 Controls Spindle Integrity, Genome Stability, and Tumor Development

Abstract

Tpx2 is a microtubule-associated protein that activates the cell-cycle kinase Aurora A and regulates the mitotic spindle. Overexpression of Tpx2 is associated with the development of different human tumors and strongly correlates with chromosomal instability. By analyzing a conditional null mutation in the mouse Tpx2 gene, we show here that Tpx2 expression is essential for spindle function and chromosome segregation in the mouse embryo. Conditional genetic ablation of Tpx2 in primary cultures resulted in deficient microtubule nucleation from DNA and aberrant spindles during prometaphase. These cells eventually exited from mitosis without chromosome segregation. In addition, Tpx2 haploinsufficiency led to the accumulation of aneuploidies in vivo and increased susceptibility to spontaneous lymphomas and lung tumors. Together, our findings indicate that Tpx2 is essential for maintaining genomic stability through its role in spindle regulation. Subtle changes in Tpx2 expression may favor tumor development in vivo. Cancer Res; 72(6); 1518-28. Ó2012 AACR.

Mitotic Stress and Chromosomal Instability in Cancer: The Case for TPX2

“…9 As expected, these We propose here that overexpression of TPX2 is likely to result in abnormal Aurora-A activity and deregulated spindle dynamics. These defects occur in the presence of abnormally high levels of MAD2, known to disrupt the normal regulation of the spindle assembly checkpoint.…”

“…5,8 The relevance of TPX2 in microtubule nucleation from the DNA has been recently corroborated using a conditional knockout model in the mouse. 9 Genetic ablation of TPX2 results in the lack of microtubule nucleation from the DNA, which implies the formation of aberrant spindles, improper chromosome segregation, and defective maintenance of the chromosomal stability (Fig. 1C).…”

“…1C), due to a specific defect in microtubule nucleation from the chromatin. 9 In addition to its critical role in spindle formation, TPX2 is thought to participate in other processes during mitosis or meiosis. TPX2 is involved in the reassembly of the nucleus of the daughter cells after mitosis in Xenopus egg extracts.…”

“…2, B and C). This binding is required for a proper localization of Aurora-A since spindle defects found in TPX2-deficient cells are accompanied by a significant reduction in the microtubule associated localization of this kinase as well as the kinesin KIF15 (mammalian homologue of Xklp 9,31,41,42 ). Aurora-A participates in spindle formation by regulating different microtubule associated proteins including the microtubule bundling factor HURP, the microtubule stabilizer XMAP215, and the microtubule destabilizing protein MCAK.…”

Targeting Protein for Xenopus Kinesin-like Protein 2 (TPX2) Regulates γ-Histone 2AX (γ-H2AX) Levels upon Ionizing Radiation

“…), and amplification of the TPX2 gene has been suggested to promote the progression of colorectal malignancies (12)(13)(14)(15)(16)(17)(18)(19). Conversely, TPX2 haploinsufficiency, leading to decreased levels of TPX2, significantly increases the propensity for the development of tumors in mice (20). Together, these results suggest that deregulation of TPX2 levels and functions are associated with the etiology of cancers.…”