title: Tumor suppressor protein DAB2IP participates in chromosomal stability maintenance through activating spindle assembly checkpoint and stabilizing kinetochore-microtubule attachments.
abstract: Defects in kinetochore-microtubule (KT-MT) attachment and the spindle assembly checkpoint (SAC) during cell division are strongly associated with chromosomal instability (CIN). CIN has been linked to carcinogenesis, metastasis, poor prognosis and resistance to cancer therapy. We previously reported that the DAB2IP is a tumor suppressor, and that loss of DAB2IP is often detected in advanced prostate cancer (PCa) and is indicative of poor prognosis. Here, we report that the loss of DAB2IP results in impaired KT-MT attachment, compromised SAC and aberrant chromosomal segregation. We discovered that DAB2IP directly interacts with Plk1 and its loss inhibits Plk1 kinase activity, thereby impairing Plk1-mediated BubR1 phosphorylation. Loss of DAB2IP decreases the localization of BubR1 at the kinetochore during mitosis progression. In addition, the reconstitution of DAB2IP enhances the sensitivity of PCa cells to microtubule stabilizing drugs (paclitaxel, docetaxel) and Plk1 inhibitor (BI2536). Our findings demonstrate a novel function of DAB2IP in the maintenance of KT-MT structure and SAC regulation during mitosis which is essential for chromosomal stability.
authors: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Lan
authors: L
authors: Yu
authors: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA School of Radiation Medicine and Protection, Medical College of Soochow University; Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou, Jiangsu 215123, China.
authors: Zeng-Fu
authors: ZF
authors: Shang
authors: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Salim
authors: S
authors: Abdisalaam
authors: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Kyung-Jong
authors: KJ
authors: Lee
authors: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Arun
authors: A
authors: Gupta
authors: Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA Department of Oncology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei 10048, Taiwan.
authors: Jer-Tsong
authors: JT
authors: Hsieh
authors: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Aroumougame
authors: A
authors: Asaithamby
authors: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA benjamin.chen@utsouthwestern.edu.
authors: Benjamin P C
authors: BP
authors: Chen
authors: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA debabrata.saha@utsouthwestern.edu.
authors: Debabrata
authors: D
authors: Saha
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D045744:Cell Line, Tumor; D043171:Chromosomal Instability; D002869:Chromosome Aberrations; D020090:Chromosome Segregation; D055786:Gene Knockout Techniques; D006801:Humans; D018386:Kinetochores / Q000378:metabolism*; D051379:Mice; D008870:Microtubules / Q000378:metabolism*; D008938:Mitosis / Q000187:drug effects / Q000235:genetics; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D034622:RNA Interference; D008941:Spindle Apparatus / Q000378:metabolism*; D050257:Tubulin Modulators / Q000494:pharmacology; D020703:ras GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D050257:Tubulin Modulators; D020703:ras GTPase-Activating Proteins; D000097869:Polo-Like Kinase 1; C462952:DAB2IP protein, human