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PNUTS) Regulates Aurora Kinases and Mitotic Progression Feifei Wang1,2,3, Ling Wang2, Laura A

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PNUTS) Regulates Aurora Kinases and Mitotic Progression Feifei Wang1,2,3, Ling Wang2, Laura A Published OnlineFirst September 6, 2018; DOI: 10.1158/1541-7786.MCR-17-0670 Cell Cycle and Senescence Molecular Cancer Research Phosphatase 1 Nuclear Targeting Subunit (PNUTS) Regulates Aurora Kinases and Mitotic Progression Feifei Wang1,2,3, Ling Wang2, Laura A. Fisher2, Chunling Li3, Weidong Wang3, and Aimin Peng2 Abstract Mitotic progression is regulated largely by reversible phos- associated proteins. PNUTS depletion suppresses the acti- phorylation events that are mediated by mitotic kinases vation of Aurora A/B kinases, and disrupts the spatiotem- and phosphatases. Protein phosphatase 1 (PP1) has been poral regulation of the chromosomal passenger complex shown to play a crucial role in regulation of mitotic entry, (CPC). PNUTS dynamically localizes to kinetochores, and progression, and exit. We previously observed, in Xenopus is required for the activation of the spindle assembly check- egg extracts, that phosphatase 1 nuclear targeting subunit point. Finally, PNUTS depletion sensitizes the tumor cell (PPP1R10/PNUTS) acts as a mitotic regulator by negatively response to Aurora inhibition, suggesting that PNUTS is a modulating PP1. This study investigates the role of PNUTS potential drug target in combination anticancer therapy. in mitotic progression in mammalian cells, and demon- strates that PNUTS expression is elevated in mitosis and Implications: Delineation of how PNUTS governs the depletion partially blocks mitotic entry. Cells that enter mitotic activation and function of Aurora kinases will mitosis after PNUTS knockdown exhibit frequent chromo- improve the understanding of the complex phospho-regu- some mis-segregation. Aurora A/B kinase complexes and lation in mitotic progression, and suggest new options to several kinetochore components are identified as PNUTS- enhance the therapeutic efficacy of Aurora inhibitors. Introduction therapy. Over the recent decade, numerous small-molecule inhi- bitors of Aurora kinases have been identified, and studies using Mitotic kinases, particularly cyclin-dependent kinase 1 these inhibitors demonstrated promising antitumor activities. (CDK1), polo-like kinase 1 (Plk1), and Aurora A/B, are well Many of these inhibitors have entered clinical trials for breast established as central regulators of mitosis. Activation of these cancer, prostate cancer, leukemia, and other malignancies (6, 8). kinases triggers the phosphorylation of various substrates to Protein phosphatases antagonize the action of kinases, but the modulate all aspects of mitotic cell reorganization and progres- function and regulation of mitotic phosphatases are considerably sion (1–4). Thus, regulated activation and deactivation of these less studied (1, 2, 4, 9–12). The two major groups of serine and kinases are defined as molecular events that dictate M-phase entry threonine phosphatases, protein phosphatase 1 (PP1) and 2A and exit. Among mitotic kinases, Aurora A and Aurora B kinases (PP2A), were both known to play important roles in mitotic phosphorylate a number of substrates to regulate the dynamics of regulation. For example, it has been shown that PP1 depho- centrosomes, microtubules, and chromatin during mitotic pro- sphorylates numerous mitotic factors and thereby regulates mitot- gression. Inactivation of Aurora A and B causes spindle defects, ic entry, metaphase–anaphase transition, chromatin condensa- chromosome missegregation, cytokinesis failure, and aneuploidy tion, and mitotic exit (13–15). A major gap in knowledge, (4–7). Owing to the crucial role of mitotic kinases in cell prolif- however, is how PP1 is regulated to achieve these dynamic and eration, and the profound toxicity of their inhibition, mitotic specific actions during mitotic progression. kinases are appreciated as potential drug targets for cancer Among the mitotic proteins dephosphorylated by PP1 were Aurora A and B kinases and their substrates, and the general role of PP1 as an antagonizer of Aurora kinases has been shown in 1Institute of Physical Science and Information Technology, Anhui University, multiple experimental systems (16–19). In yeast, the codeletion Hefei, China. 2Department of Oral Biology, College of Dentistry, University of of PP1/Glc7 with Aurora/Ipl1 rescued mitotic progression and cell Nebraska Medical Center, Lincoln, Nebraska. 3Institute of Hypertension, proliferation from Aurora/Ipl1 deletion (16). Similarly, PP1 Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China. suppression in mammalian cells prevented mitotic defects Note: Supplementary data for this article are available at Molecular Cancer induced by the inhibition of Aurora B (17–19). The opposing Research Online (http://mcr.aacrjournals.org/). relationship between PP1 and Aurora is perhaps best illustrated in Corresponding Author: Aimin Peng, Department of Oral Biology, College of the regulation of spindle assembly checkpoint signaling at kine- Dentistry, University of Nebraska Medical Center, 40th & Holdrege, Lincoln, NE tochores. The spindle checkpoint is a surveillance mechanism that 68516. Phone: 402-472-5903; Fax: 402-472-2551; ensures the proper, bipolar kinetochore–microtubule attach- E-mail: [email protected] ments (20, 21). It has been shown that reversible phosphorylation doi: 10.1158/1541-7786.MCR-17-0670 of kinetochore components plays a pivotal role in governing Ó2018 American Association for Cancer Research. spindle attachment and the activation/deactivation of the spindle 10 Mol Cancer Res; 17(1) January 2019 Downloaded from mcr.aacrjournals.org on September 29, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst September 6, 2018; DOI: 10.1158/1541-7786.MCR-17-0670 Aurora Kinases and Mitosis Are Regulated by PNUTS checkpoint (22). On one hand, centromeric Aurora B is respon- Immunoblotting and immunoprecipitation sible for the activation of the spindle checkpoint via both the SDS-PAGE and immunoblotting were performed as described recruitment of spindle checkpoint kinases, such as Mps1 and previously (36). For immunoprecipitation, anti-rabbit magnetic Bub1, and the subsequent phosphorylation of BubR1, Mad1, beads (New England Biolabs) were conjugated to the primary Ndc80/Hec1, Knl1, and other kinetochore proteins (21, 22). On antibody, and then incubated in cell lysates for 2 hours. The beads the other hand, several kinetochore components, especially Knl1, were collected using a magnet, washed, eluted with Laemmli yield PP1-binding activities, and were reported to recruit PP1 to sample buffer, and then analyzed by immunoblotting. kinetochores (19). After the proper spindle–kinetochore attach- ment, PP1 dephosphorylates Aurora B, Knl1, BubR1, and other Immunofluorescence and imaging kinetochore proteins to silence the spindle checkpoint and trigger Immunofluorescence was performed as described previously metaphase–anaphase transition (22). (37). Briefly, cells were fixed in a fixation buffer (3% formalde- Phosphatase 1 nuclear subunit (PNUTS), also known as hyde with 0.1% Triton X-100), washed, and blocked in a blocking PPP1R10, was originally described as a nuclear regulator of PP1 buffer (10% goat serum in PBS). The primary antibodies were that retains a portion of PP1 in the nucleus (23). PNUTS has been diluted in the blocking buffer, and incubated with the cells for implicated in transcription and RNA processing (24, 25), DNA 2 hours. The cells were then washed, and incubated with the Alexa – damage response and maintenance of telomere stability (26 30), Fluor 594 and 488 secondary antibodies (Invitrogen) for 1 hour. and modulation of RB and PTEN (31–33). In most cases, with the Imaging was performed using a Zeiss Axiovert 200M inverted fi exception of RNA Pol II, PNUTS acts to inhibit PP1 toward speci c fluorescence microscope at the UNMC Advanced Microscopy substrates. The earliest evidence that linked PNUTS to mitosis Core Facility. Live-cell imaging was performed using the Marianas in vitro came from the observation that PNUTS enhanced the Live Cell system based around a Zeiss Axiovert 200M microscope chromosome decondensation in a PP1-dependent manner (34). stand, and the SlideBook6 software (Intelligent Imaging Innova- Xenopus Interestingly, our recent study in egg extracts suggested a tions, Inc.). Images were collected with 10Â objective lens mag- role of PNUTS as an essential regulator of mitotic progression. nification. Once the live-cell microscopy was completed, the Overexpression of PNUTS in Xenopus egg extracts inhibited mitot- captured images were loaded into SlideBook Reader Software ic exit. PNUTS depletion disrupted mitotic maintenance, whereas (Intelligent Imaging Innovations). codepletion of PP1 rescued the defect (35). The level of PNUTS oscillated in cycling extracts and peaked in mitosis. In this study, we sought to examine the role of PNUTS in human cells, and to Protein expression, pull-down, and mass spectrometry analysis reveal further mechanistic insights into how PNUTS governs MBP-tagged PNUTS was constructed and expressed as in our mitotic signaling. Our results confirmed a role of PNUTS in previous study (35). The recombinant protein was expressed in mammalian mitotic progression, characterized PNUTS-mediated BL21 bacterial cells and purified on amylose beads. For the pull- regulation of Aurora kinases and spindle checkpoint signaling, down assay, amylose beads conjugated with MBP–PNUTS were and suggested PNUTS as a potential target to enhance the cyto- incubated in Xenopus egg extracts that were prepared as in our toxicity of Aurora inhibitors. previous study (35).
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