title: Depletion of tumor suppressor Kank1 induces centrosomal amplification via hyperactivation of RhoA.
abstract: Chromosome instability, frequently found in cancer cells, is caused by a deficiency in cell division, including centrosomal amplification and cytokinesis failure, and can result in abnormal chromosome content or aneuploidy. The small GTPase pathways have been implicated as important processes in cell division. We found that knockdown of a tumor suppressor protein Kank1 increases the number of cells with a micronucleus or bi-/multi-nuclei, which was likely caused by centrosomal amplification. Kank1 interacts with Daam1, known to bind to and activate a small GTPase, RhoA, in actin assembly. Knockdown of Kank1 or overexpression of Daam1, respectively, hyperactivates RhoA, potentially leading to the modulation of the activity of Aurora-A, a key regulator of centrosomal functions, eventually resulting in centrosomal amplification. Kank1 is also associated with contractile ring formation in collaboration with RhoA, and its deficiency results in the interruption of normal daughter cell separation, generating multinucleate cells. Such abnormal segregation of chromosomes may cause further chromosomal instability and abnormal gene functions, leading to tumorigenesis. Thus, Kank1 plays a crucial role in regulating the activity of RhoA through retrieving excess Daam1 and balancing the activities of RhoA and its effectors.
authors.affiliation: Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki 305-8566, Japan.
authors.forename: Jun-Ichiro
authors.initials: JI
authors.lastname: Suzuki
authors.affiliation: Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki 305-8566, Japan.
authors.forename: Badal Chandra
authors.initials: BC
authors.lastname: Roy
authors.affiliation: Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki 305-8566, Japan.
authors.forename: Takunori
authors.initials: T
authors.lastname: Ogaeri
authors.affiliation: Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki 305-8566, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Kakinuma
authors.affiliation: Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki 305-8566, Japan. Electronic address: kiyama.r@aist.go.jp.
authors.forename: Ryoiti
authors.initials: R
authors.lastname: Kiyama
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D064096:Aurora Kinase A / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics*; D002455:Cell Division / Q000235:genetics; D018385:Centrosome / Q000378:metabolism; D043171:Chromosomal Instability / Q000235:genetics; D020090:Chromosome Segregation / Q000235:genetics; D003598:Cytoskeletal Proteins; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008840:Microfilament Proteins; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; C499094:DAAM1 protein, human; C467739:KANK1 protein, human; D008840:Microfilament Proteins; D025521:Tumor Suppressor Proteins; C066737:RHOA protein, human; D064096:Aurora Kinase A; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein
keywords: Cell division; Centrosome; Chromosome instability; Small GTPase; Tumor suppressor