title: Therapeutic potential of mitotic interaction between the nucleoporin Tpr and aurora kinase A.
abstract: Spindle poles are defined by centrosomes; therefore, an abnormal number or defective structural organization of centrosomes can lead to loss of spindle bipolarity and genetic integrity. Previously, we showed that Tpr (translocated promoter region), a component of the nuclear pore complex (NPC), interacts with Mad1 and dynein to promote proper chromosome segregation during mitosis. Tpr also associates with p53 to induce autophagy. Here, we report that Tpr depletion induces mitotic catastrophe and enhances the rate of tetraploidy and polyploidy. Mechanistically, Tpr interacts, via its central domain, with Aurora A but not Aurora B kinase. In Tpr-depleted cells, the expression levels, centrosomal localization and phosphorylation of Aurora A were all reduced. Surprisingly, an Aurora A inhibitor, Alisertib (MLN8237), also disrupted centrosomal localization of Tpr and induced mitotic catastrophe and cell death in a time- and dose-dependent manner. Strikingly, over-expression of Aurora A disrupted Tpr centrosomal localization only in cells with supernumerary centrosomes but not in bipolar cells. Our results highlight the mutual regulation between Tpr and Aurora A and further confirm the importance of nucleoporin function in spindle pole organization, bipolar spindle assembly, and mitosis; functions that are beyond the conventional nucleocytoplasmic transport and NPC structural roles of nucleoporins. Furthermore, the central coiled-coil domain of Tpr binds to and sequesters extra Aurora A to safeguard bipolarity. This Tpr domain merits further investigation for its ability to inhibit Aurora kinase and as a potential therapeutic agent in cancer treatment.
authors: a Laboratory of Molecular and Cellular Biology; Department of Biology ; Faculty of Natural Systems; Kanazawa University ; Kanazawa , Ishikawa , Japan.
authors: Akiko
authors: A
authors: Kobayashi
authors: Chieko
authors: C
authors: Hashizume
authors: Takayuki
authors: T
authors: Dowaki
authors: Richard W
authors: RW
authors: Wong
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D059447:Cell Cycle Checkpoints; D018385:Centrosome / Q000187:drug effects / Q000201:enzymology*; D020090:Chromosome Segregation; D006367:HeLa Cells; D006801:Humans; D008938:Mitosis / Q000187:drug effects; D028861:Nuclear Pore Complex Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D057891:Tetraploidy; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D028861:Nuclear Pore Complex Proteins; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; C073597:TPR protein, human; C576917:AURKA protein, human; D064096:Aurora Kinase A
keywords: AURKA; alisertib; centriole; centrosome; tpr