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RACK1 Regulates Centriole Duplication Through Promoting the Activation Of © 2020. Published by The Company of Biologists Ltd | Journal of Cell Science (2020) 133, jcs238931. doi:10.1242/jcs.238931 RESEARCH ARTICLE RACK1 regulates centriole duplication through promoting the activation of polo-like kinase 1 by Aurora A Yuki Yoshino1,2,3,*, Akihiro Kobayashi1,2,*, Huicheng Qi1,2, Shino Endo1,2, Zhenzhou Fang1,2, Kazuha Shindo1,3, Ryo Kanazawa1,3 and Natsuko Chiba1,2,3,‡ ABSTRACT Centrosomes consist of a pair of centrioles, termed the mother Breast cancer gene 1 (BRCA1) contributes to the regulation of centriole and the daughter centriole, and proteinaceous centrosome number. We previously identified receptor for activated C pericentriolar material surrounding the mother centriole (Conduit kinase 1 (RACK1) as a BRCA1-interacting partner. RACK1, a scaffold et al., 2015). The proper number of centrosomes is stably protein that interacts with multiple proteins through its seven WD40 maintained by a regulatory network that ensures duplication only domains, directly binds to BRCA1 and localizes to centrosomes. once per cell cycle (Conduit et al., 2015; Fujita et al., 2016; Nigg RACK1 knockdown suppresses centriole duplication, whereas and Holland, 2018). At entry into mitosis, a cell has two RACK1 overexpression causes centriole overduplication in a subset centrosomes, each containing a pair of tightly engaged centrioles. of mammary gland-derived cells. In this study, we showed that During mitosis, centrioles lose their connection in a process termed RACK1 binds directly to polo-like kinase 1 (PLK1) and Aurora A, and disengagement, and the two centrioles are joined by a flexible promotes the Aurora A–PLK1 interaction. RACK1 knockdown linker. In late G1 phase of the following cell cycle, a new daughter decreased phosphorylated PLK1 (p-PLK1) levels and the centrosomal centriole is generated on the side wall of each mother centriole. The localization of Aurora A and p-PLK1 in S phase, whereas RACK1 daughter centrioles grow during S phase, resulting in the formation overexpression increased p-PLK1 level and the centrosomal localization of two pairs of centrioles in two centrosomes in G2 phase. In late G2 of Aurora A and p-PLK1 in interphase, resulting in an increase of cells phase, the linker is degraded and the two centrosomes separate to with abnormal centriole disengagement. Overexpression of cancer- form bipolar spindles. derived RACK1 variants failed to enhance the Aurora A–PLK1 During centriole duplication, the newly formed daughter centrioles interaction, PLK1 phosphorylation and the centrosomal localization of suppress the formation of additional daughter centrioles to prevent p-PLK1. These results suggest that RACK1 functions as a scaffold multiple rounds of duplication (Tsou and Stearns, 2006a; Nigg, 2007). protein that promotes the activation of PLK1 by Aurora A in order to Although the mechanism underlying this suppression is poorly promote centriole duplication. understood, disengagement is thought to release the suppression (Tsou and Stearns, 2006a; Nigg, 2007; Shukla et al., 2015). Therefore, This article has an associated First Person interview with the first author the timing of disengagement is important for the regulation of of the paper. centriole duplication to maintain the proper number of centrosomes. Centrosome amplification, a common condition in many cancers, KEY WORDS: Aurora A, PLK1, Cancer, Centriole duplication, including breast cancer (Chan, 2011), is associated with chromosomal Centrosome instability and aggressive phenotypes (Denu et al., 2016; Godinho et al., 2014; Schneeweiss et al., 2003). Breast cancer gene 1 (BRCA1) INTRODUCTION mutations are responsible for hereditary breast and ovarian cancer The centrosome is a major microtubule organizing center and syndrome, and loss or mutation of BRCA1 causes centrosome facilitates proper bipolar spindle formation (Conduit et al., 2015). amplification (Starita et al., 2004; Ko et al., 2006). Certain BRCA1 An abnormal number of centrosomes causes aberrant cell division variants found in familial breast cancers are associated with (e.g. monopolar and multipolar division) and chromosome deficiencies in the regulation of centrosome number (Kais et al., segregation errors, leading to carcinogenesis (Milunovic-Jevtić ́ 2012). BRCA1 germline mutation and negative expression of BRCA1 et al., 2016; Cosenza et al., 2017; Levine et al., 2017). Therefore, the are significantly associated with centrosome amplification in breast regulation of centrosome number is important for the maintenance cancer tissues (Shimomura et al., 2009; Watanabe et al., 2018). of chromosomal stability and tumor suppression. BRCA1 forms multi-protein complexes with BRCA1-associated RING domain protein 1 (BARD1) and other proteins that function in a number of cellular processes, including DNA repair and 1Department of Cancer Biology, Institute of Aging, Development, and Cancer, centrosome regulation (Takaoka and Miki, 2018). In previous Tohoku University, 4-1 Seiryomachi, Aoba-ku, Sendai 980-8575, Japan. studies, we identified Obg-like ATPase 1 (OLA1) (Matsuzawa et al., 2Department of Cancer Biology, Tohoku University Graduate School of Medicine, 4-1 Seiryomachi Aoba-ku, Sendai 980-8575, Japan. 3Laboratory of Cancer Biology, 2014; Yoshino et al., 2018) and receptor for activated C kinase 1 Graduate School of Life Sciences, Tohoku University, 4-1 Seiryomachi Aoba-ku, (RACK1) (Yoshino et al., 2019) as components of the BRCA1– Sendai 980-8575, Japan. BARD1 complex. OLA1 localizes to centrosomes and directly *These authors contributed equally to this work binds to BRCA1, BARD1 and γ-tubulin. Knockdown or ‡Author for correspondence ([email protected]) overexpression of OLA1 increases the fraction of cells with centrosome amplification caused by centriole overduplication in Y.Y., 0000-0003-0029-3467; N.C., 0000-0001-6504-1290 mammary tissue-derived cells (Matsuzawa et al., 2014; Yoshino Handling Editor: David Glover et al., 2018). RACK1 also localizes to centrosomes and directly Received 7 September 2019; Accepted 29 July 2020 binds to BRCA1, OLA1 and γ-tubulin, and interacts with BARD1. Journal of Cell Science 1 RESEARCH ARTICLE Journal of Cell Science (2020) 133, jcs238931. doi:10.1242/jcs.238931 Knockdown of RACK1 suppresses centriole duplication in some each cell cycle phase. MCF7 cells were transfected with control or breast cancer cells. Conversely, overexpression of RACK1 increases HA–RACK1 vector and synchronized to the G1/S transition by a the fraction of cells with centrosome amplification caused by double thymidine block (Fig. 1B, Protocol 1). Then, cells were centriole overduplication in mammary tissue-derived cells. released into fresh medium and fixed for immunocytofluorescence Adequate RACK1 expression levels contribute to the proper with anti-HA and γ-tubulin antibodies after 0, 4, 8, and 12 h of localization of BRCA1 to centrosomes. Alterations in the incubation, which represented G1/S transition (G1/S), S, G2, and expression levels or missense mutations of OLA1 and RACK1 are G1 phases, respectively (Fig. 1C). RACK1-OE cells were identified associated with various cancers, as reported in the COSMIC as HA-positive cells and subjected to analysis of centrosome database (https://cancer.sanger.ac.uk/cosmic). These data suggest number. Cells with amplified (more than two) centrosomes that the centrosomal BRCA1–BARD1 complex containing OLA1 were counted, and their percentage was calculated. RACK1 and RACK1 is important for the regulation of centrosome number overexpression significantly increased the proportion of cells with and tumor suppression. However, the underlying molecular centrosome amplification in S and G2 cells, but not in G1 and G1/S mechanism remains unknown. cells (Fig. 1D,E). These data indicate that the centrosome Centriole duplication is regulated by several mitotic kinases (Wang amplification observed in RACK1-OE cells occurred during S et al., 2014; Nigg and Holland, 2018). Polo-like kinase 1 (PLK1) is a and G2 phases. critical regulator of centriole disengagement during mitosis (Tsou To confirm that RACK1 overexpression induces centriole et al., 2009; Shukla et al., 2015), and its activity is tightly regulated overduplication in MCF7 cells, as previously observed in spatially and temporally throughout the cell cycle. Aurora A kinase Hs578T cells (Yoshino et al., 2019), we stained the centriole phosphorylates PLK1 at Thr210 under the control of CDK1 and Bora with anti-CP110 antibody, the mother centriole with anti-CEP152 to activate PLK1 in late G2 phase and initiate mitotic entry (Macurek antibody, and the daughter centriole with anti-SAS6 antibody in et al., 2008; Schmucker and Sumara, 2014; Seki et al., 2008; RACK1-OE MCF7 cells (Fig. S1A). RACK1 overexpression Bruinsma et al., 2014). In centrosomes, PLK1 activation by Aurora A increased the fraction of cells with a CP110 foci/CEP152 foci ratio and the scaffold protein CEP192 is essential for centrosome of >2 (Fig. S1B,D) and that of cells with extra SAS6 foci that did maturation and bipolar spindle formation during G2 and mitotic not pair with CEP152 foci (Fig. S1C,D). These results suggest that phases (Joukov et al., 2014; Meng et al., 2015). In addition, PLK1 centriole overduplication is also induced in some RACK1-OE contributes to centrosome amplification induced by S phase or G2 MCF7 cells. arrest or DNA damage (Loncareǩ et al., 2010; Zou et al., 2014). PLK4, another member of the PLK family, is essential for centriole PLK1, Aurora A and PLK4 activities contribute to duplication
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