Details of a Researcher - Saya, Hideyuki

Papers - Saya, Hideyuki

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Identification of tumor-initiating cells in a highly aggressive brain tumor using promoter activity of nucleostemin

Tamase Akira, Muraguchi Teruyuki, Naka Kazuhito, Tanaka Shingo, Kinoshita Masashi, Hoshii Takayuki, Ohmura Masako, Shugo Haruhiko, Ooshio Takako, Nakada Mitsutoshi, Sawamoto Kazunobu, Onodera Masafumi, Matsumoto Kunio, Oshima Masanobu, Asano Masahide, Saya Hideyuki, Okano Hideyuki, Suda Toshio, Hamada Jun Ichiro, Hirao Atsushi

Proceedings of the National Academy of Sciences of the United States of America 106 ( 40 ) 17163 - 17168 2009.10

ISSN 0027-8424

Controversy remains over whether the cancer stem cell (CSC) theory applies to all tumors. To determine whether cells within a highly aggressive solid tumor are stochastically or hierarchically organized, we combined a reporter system where the nucleostemin (NS) promoter drives GFP expression (termed NS-GFP) with a mouse brain tumor model induced by retroviral Ras expression on a p16 ^Ink4a/p19^Arf-deficient background. The NS-GFP system allowed us to monitor the differentiation process of normal neural stem/precursor cells by analyzing GFP fluorescence intensity. In tumor-bearing mice, despite the very high frequency of tumorigenic cells, we successfully identified the NS-GFP⁺ cells as tumorinitiating cells (T-ICs). The clonal studies conclusively established that phenotypical heterogeneity can exist among the cells comprising a genetically homogeneous tumor, suggesting that this aggressive brain tumor follows the CSC model. Detailed analyses of the NS-GFP⁺ brain tumor cells revealed that T-ICs showed activation of the receptor tyrosine kinase c-Met, which functions in tumor invasiveness. Thus, the NS-GFP system provides a powerful tool to elucidate stem cell biology in normal and malignant tissues.

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Current clinical trials using new targeted therapies for myeloid leukemia and the research trends

Ishizawa J., Saya Hideyuki

Nippon rinsho. Japanese journal of clinical medicine 67 ( 10 ) 1932 - 1937 2009.10

ISSN 0047-1852

Great progress on insight into genetic aberrations of myeloid leukemia via gene expression profiling has led to better understanding of the pathobiology of this heterogeneous disorder. It enabled the development of specific treatment modalities targeted to underlying oncogenic abnormalities, with well established examples of all-trans retinoic acid for the treatment of acute promyelocytic leukemia and imatinib for chronic myeloid leukemia. However, these strategies have not been completely developed yet in that most of brand new targeted therapies have been somewhat far from achieving cure of leukemia and that many problems with regards to drug resistance and recurrence from minimal residual disease remain to be solved. On the other hand, concept of cancer(leukemic) stem cell and its niche has been shedding new light on oncological field these days. This review summarizes the current clinical trials using new targeted therapies and research trends on myeloid leukemia.

Simian virus 40 large T antigen targets the microtubule-stabilizing protein TACC2

Tei Shuchin, Saitoh Noriko, Funahara Tetsushi, Iida Shin Ichi, Nakatsu Yuko, Kinoshita Kayo, Kinoshita Yoshikazu, Saya Hideyuki, Nakao Mitsuyoshi

Journal of Cell Science 122 ( 17 ) 3190 - 3198 2009.09

ISSN 0021-9533

The large T antigens of polyomaviruses target cellular proteins that control fundamental processes, including p53 and the RB family of tumor suppressors. Mechanisms that underlie Tantigen- induced cell transformation need to be fully addressed, because as-yet unidentified target proteins might be involved in the process. In addition, recently identified polyomaviruses are associated with particular human diseases such as aggressive skin cancers. Here, we report that simian virus 40 (SV40) large T antigen interacts with the transforming acidic coiled-coilcontaining protein TACC2, which is involved in stabilizing microtubules in mitosis. T antigen directly binds TACC2 and induces microtubule dysfunction, leading to disorganized mitotic spindles, slow progression of mitosis and chromosome missegregation. These mitotic defects are caused by N-terminaldeleted T antigen, which minimally interacts with TACC2, whereas T-antigen-induced microtubule destabilization is suppressed by overexpressing TACC2. Thus, TACC2 might be a key target of T antigen to disrupt microtubule regulation and chromosomal inheritance in the initiation of cell transformation.

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Real-time in vivo imaging of p16^Ink4a reveals cross talk with p53

Yamakoshi Kimi, Takahashi Akiko, Hirota Fumiko, Nakayama Rika, Ishimaru Naozumi, Kubo Yoshiaki, Mann David J., Ohmura Masako, Hirao Atsushi, Saya Hideyuki, Arase Seiji, Hayashi Yoshio, Nakao Kazuki, Matsumoto Mitsuru, Ohtani Naoko, Hara Eiji

Journal of Cell Biology 186 ( 3 ) 393 - 407 2009.08

ISSN 0021-9525

Expression of the p16^Ink4a tumor suppressor gene, a sensor of oncogenic stress, is up-regulated by a variety of potentially oncogenic stimuli in cultured primary cells. However, because p16^Ink4a expression is also induced by tissue culture stress, physiological mechanisms regulating p16^Ink4a expression remain unclear. To eliminate any potential problems arising from tissue culture-imposed stress, we used bioluminescence imaging for noninvasive and real-time analysis of p16^Ink4a expression under various physiological conditions in living mice. In this study, we show that oncogenic insults such as ras activation provoke epigenetic derepression of p16^Ink4a expression through reduction of DNMT1 (DNA methyl transferase 1) levels as a DNA damage response in vivo. This pathway is accelerated in the absence of p53, indicating that p53 normally holds the p16^Ink4a response in check. These results unveil a backup tumor suppressor role for p16^Ink4a in the event of p53 inactivation, expanding our understanding of how p16^Ink4a expression is regulated in vivo.

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BubR1 localizes to centrosomes and suppresses centrosome amplification via regulating Plk1 activity in interphase cells

Izumi H., Matsumoto Y., Ikeuchi T., Saya H., Kajii T., Matsuura S.

Oncogene 28 ( 31 ) 2806 - 2820 2009.08

ISSN 0950-9232

BubR1 is a critical component of the mitotic checkpoint that delays the onset of anaphase until all chromosomes have established bipolar attachment to the microtubules. We previously reported that mutations of the BUB1B gene (encoding BubR1) caused premature chromatid separation (PCS) syndrome, a condition characterized by constitutional aneuploidy and a high risk of childhood cancer. We here report that the cells from PCS syndrome patients have loss of regulation of the centrosome duplication machinery, resulting in centrosome amplification and multipolar mitosis. PCS syndrome cells show increased activity of Polo-like kinase 1 (Plk1), whose knockdown suppresses centrosome amplification. BubR1 localizes to centrosomes, physically interacts with Plk1 and inhibits Plk1 phosphorylation and its kinase activity during interphase. These results unravel a crucial role of BubR1 in preventing centrosome reduplication through negative regulation of Plk1 in interphase cells.

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Molecular mechanism of cell death induced by chemotherapeutic agents

Saya Hideyuki

Brain and Nerve 61 ( 7 ) 843 - 847 2009.07

ISSN 1881-6096

Cells maintain their homeostasis by checkpoint mechanisms that exist at each phase of the cell cycle. Impairment of the checkpoint mechanisms induces DNA mutation and asymmetric segregation of chromosomes, which result in genomic instability, leading to malignant cell transformation. DNA-damaging agents, which are still the first-line chemotherapeutic drugs for various cancers, have recently been demonstrated to induce death in cancer cells alone just because these cells have abnormalities in their checkpoint mechanisms. The mitotic checkpoint, in particular, has been found to play a key role in the drug-induced cell death. An understanding of the molecular mechanisms of chemotherapy will enable us to use conventional drugs more appropriately for cancer treatment.

Overexpression of Aurora A by loss of CHFR gene expression increases the growth and survival of HTLV-1-infected T cells through enhanced NF-κB activity

Tomita Mariko, Toyota Minoru, Ishikawa Chie, Nakazato Tetsuro, Okudaira Taeko, Matsuda Takehiro, Uchihara Jun Nosuke, Taira Naoya, Ohshiro Kazuiku, Senba Masachika, Tanaka Yuetsu, Ohshima Koichi, Saya Hideyuki, Tokino Takashi, Mori Naoki

International Journal of Cancer 124 ( 11 ) 2607 - 2615 2009.06

ISSN 0020-7136

Human T-cell leukemia virus type 1 (HTLV-1) is the etiologic agent for adult T-cell leukemia (ATL). Aurora A, a mitotic checkpoint protein, is overexpressed in human cancer cells. The cell cycle-dependent turnover of Aurora A is regulated by E3 ubiquitin ligases such as checkpoint with fork head-associated and ring finger (CHFR). Here, we found overexpression of Aurora A protein in HTLV-1-infected T-cell lines and primary ATL cells. The expression of CHFR mRNA was reduced in these cells by abnormal methylation of CHFR promoter region. Knockdown of Aurora A using small interfering RNA suppressed the growth of HTLV-1-infected T-cell line. Transfection of Aurora A expression plasmid enhanced Tax-induced nuclear factor-κB (NF-κB) reporter activity. Transfection of CHFR expression plasmid into an HTLV-1-infected T-cell line reduced cell growth, Aurora A protein level and constitutive NF-κB reporter activity. Aurora kinase inhibitor suppressed the growth and survival of HTLV-1-infected T-cell lines and primary ATL cells. It also reduced constitutive NF-κB activity in an HTLV-1-infected T-cell line by reducing IκB kinase κ phosphorylation and the expression of antiapoptotic protein survivin. Our results suggested that loss of CHFR expression resulted to accumulation of Aurora A, which increased NF-κB activity. These findings highlight the critical role of Aurora A in HTLV-1-infected T cells, making this molecule a potentially suitable target for future therapies for ATL.

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M-CSF inhibition selectively targets pathological angiogenesis and lymphangiogenesis

Kubota Yoshiaki, Takubo Keiyo, Shimizu Takatsune, Ohno Hiroaki, Kishi Kazuo, Shibuya Masabumi, Saya Hideyuki, Suda Toshio

Journal of Experimental Medicine 206 ( 5 ) 1089 - 1102 2009.05

ISSN 0022-1007

Antiangiogenic therapy for the treatment of cancer and other neovascular diseases is desired to be selective for pathological angiogenesis and lymphangiogenesis. Macrophage colony-stimulating factor (M-CSF), a cytokine required for the differentiation of monocyte lineage cells, promotes the formation of high-density vessel networks in tumors and therefore possesses therapeutic potential as an M-CSF inhibitor. However, the physiological role of M-CSF in vascular and lymphatic development, as well as the precise mechanisms underlying the antiangiogenic effects of M-CSF inhibition, remains unclear. Moreover, therapeutic potential of M-CSF inhibition in other neovascular diseases has not yet been evaluated. We used osteopetrotic (op/op) mice to demonstrate that M-CSF deficiency reduces the abundance of LYVE-1⁺ and LYVE1^- macrophages, resulting in defects in vascular and lymphatic development. In ischemic retinopathy, M-CSF was required for pathological neovascularization but was not required for the recovery of normal vasculature. In mouse osteosarcoma, M-CSF inhibition effectively suppressed tumor angiogenesis and lymphangiogenesis, and it disorganized extracellular matrices. In contrast to VEGF blockade, interruption of M-CSF inhibition did not promote rapid vascular regrowth. Continuous M-CSF inhibition did not affect healthy vascular and lymphatic systems outside tumors. These results suggest that M-CSF-targeted therapy is an ideal strategy for treating ocular neovascular diseases and cancer.

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K858, a novel inhibitor of mitotic kinesin Eg5 and antitumor agent, induces cell death in cancer cells

Nakai Ryuichiro, Iida Shin Ichi, Takahashi Takeshi, Tsujita Tetsuya, Okamoto Seiho, Takada Chie, Akasaka Kazuhito, Ichikawa Shunji, Ishida Hiroyuki, Kusaka Hideaki, Akinaga Shiro, Murakata Chikara, Honda Shinobu, Nitta Masayuki, Saya Hideyuki, Yamashita Yoshinori

Cancer Research 69 ( 9 ) 3901 - 3909 2009.05

ISSN 0008-5472

The aim of this study was to investigate the mechanism of inhibition of Eg5 (kinesin spindle protein), a mitotic kinesin that plays an essential role in establishing mitotic spindle bipolarity, by the novel small molecule inhibitor K858. K858 was selected in a phenotype-based forward chemical genetics screen as an antimitotic agent, and subsequently characterized as an inhibitor of Eg5. K858 blocked centrosome separation, activated the spindle checkpoint, and induced mitotic arrest in cells accompanied by the formation of monopolar spindles. Long-term continuous treatment of cancer cells with K858 resulted in antiproliferative effects through the induction of mitotic cell death, and polyploidization followed by senescence. In contrast, treatment of nontransformed cells with K858 resulted in mitotic slippage without cell death, and cell cycle arrest in G₁ phase in a tetraploid state. In contrast to paclitaxel, K858 did not induce the formation of micronuclei in either cancer or nontransformed cells, suggesting that K858 has minimal effects on abnormalities in the number and structure of chromosomes. K858 exhibited potent antitumor activity in xenograft models of cancer, and induced the accumulation of mitotic cells with monopolar spindles in tumor tissues. Importantly, K858, unlike antimicrotubule agents, had no effect on microtubule polymerization in cell-free and cellbased assays, and was not neurotoxic in a motor coordination test in mice. Taken together, the Eg5 inhibitor K858 represents an important compound for further investigation as a novel anticancer therapeutic.

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[Mitotic regulation and carcinogenesis].

Saya Hideyuki, Zhang Dongwei, Oltea Sampetrean

Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme 54 ( 4 Suppl ) 561 - 567 2009.03

ISSN 0039-9450

Reversible whole-organism cell cycle arrest in a living vertebrate

Sampetrean Oltea, Lida Shin Ichi, Makino Shinji, Matsuzaki Yuriko, Ohno Kikuo, Saya Hideyuki

Cell Cycle 8 ( 4 ) 620 - 627 2009.02

ISSN 1538-4101

In vivo cell cycle analysis in higher eukaryotes has been limited by the challenge of preserving the integrity of the living organism while visualizing dividing cells. Japanese medaka in order to visualize and manipulate the cell cycle progression in a live vertebrate. Our stable transgenic histone H2B-GFP medaka line allows fluorescence-based monitoring of the chromosomes. The system has a high specificity, with a strong GFP signal labeling the chromatin architecture. The subcellular resolution ensures detection of both normal and abnormal divisions in live recordings. This translates into the possibility to quantify temporal and spatial aspects of the cell cycle, such as length or nuclear size, as well as to expose drug toxicity at the earliest stage. We also show that acclimation to cold, a prominent feature of the eurytherm medaka, is a valuable natural way of inducing a reversible cell cycle arrest in the entire living organism. Our results suggest that this manipulation can be performed from the early stages of development, has no toxicity and does not alter the cell cycle profile of the embryo.

Molecular mechanism regulating effect of anti-cancer agents

Saya Hideyuki

Japanese Journal of Cancer and Chemotherapy 36 ( 1 ) 1 - 5 2009.01

ISSN 0385-0684

Faithful genome duplication is achieved by accurate coordination between DNA replication and chromosome segregation. Abnormalities occurring in this process are checked by biochemical signal transduction pathways, called checkpoints, which ensure the orderly progression of events in the cell cycle. Checkpoints prevent transition into subsequent phases until all processes in the previous phase are completed. Defects in cell cycle checkpoints result in gene mutations, chromosome damage, and aneuploidy, all of which contribute to tumorigenesis. However, it has recently been uncovered that the impairment of checkpoint function is the major reason why DNA damaging anti-cancer agents can selectively kill cancer cells. Given that G₁ and G₂ checkpoint functions are generally impaired in cancer cells, cells with DNA damage are unable to maintain G₂ arrest and eventually die as they enter mitosis. This process is known as mitotic catastrophe.

Molecular mechanisms regulating dissociation of cell-cell junction of epithelial cells by oxidative stress

Inumaru Junko, Nagano Osamu, Takahashi Eri, Ishimoto Takatsugu, Nakamura Satoshi, Suzuki Yoshimi, Niwa Shin Ichiro, Umezawa Kazuo, Tanihara Hidenobu, Saya Hideyuki

Genes to Cells 14 ( 6 ) 703 - 716 2009

ISSN 1356-9597

Oxidative stress is regarded as a causative factor in aging and various degenerative diseases. Here, we show the mechanism by which oxidative stress induces disruption of cell-cell junctions using retinal pigment epithelial cells. We demonstrated that reactive oxygen species (ROS)-mediated activation of Src kinase increases the tyrosine phosphorylation state of p120-catenin and rapidly triggers translocation of p120-catenin and internalization of N-cadherin from the cell-cell adhesion sites to an early endosomal compartment. Endosomal accumulation of p120-catenin resulted in stress fiber formation and cell-cell dissociation through the activation of Rho/Rho kinase pathway. However, these cytoskeletal remodeling and cell-cell dissociation induced by oxidative stress were transient, due to the activation of nuclear factor-κB (NF-κB) and the expression of manganese superoxide dismutase (Mn-SOD). Using the NF-κB specific inhibitor DHMEQ, we found that NF-κB is part of a negative feedback loop to control intracellular ROS levels. Finally, we demonstrated that H₂ O₂ treatment alone does not induce the epithelial mesenchymal transition (EMT) in retinal pigment epithelial cells, which can be induced by TNF-α treatment. These findings suggest that oxidative stress is a crucial factor to induce the cell-cell dissociation, an initial step of EMT, but does not provide sufficient signals to establish and to maintain the EMT.

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Brain tumor stem cells from an adenoid glioblastoma multiforme

Saya Hideyuki

Neurologia Medico-Chirurgica 49 ( 4 ) 151 2009

ISSN 0470-8105

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Involvement of hyaluronan and its receptor CD44 with choroidal neovascularization

Mochimaru Hiroshi, Takahashi Eri, Tsukamoto Nobuo, Miyazaki Junichiro, Yaguchi Tomonori, Koto Takashi, Kurihara Toshihide, Noda Kousuke, Ozawa Yoko, Ishimoto Takatsugu, Kawakami Yutaka, Tanihara Hidenobu, Saya Hideyuki, Ishida Susumu, Tsubota Kazuo

Investigative Ophthalmology and Visual Science 50 ( 9 ) 4410 - 4415 2009

ISSN 0146-0404

PURPOSE. CD44 is a cell-surface adhesion molecule and receptor for hyaluronan (HA), one of the major extracellular matrix components. The purpose of the present study was to clarify a role of HA and CD44 in the development of choroidal neovascularization (CNV). METHODS. Laser photocoagulation was used to induce CNV in C57BL/6 mice or CD44-deficient mice. The mRNA expression of CD44 and HA synthase (HAS)-2 in the retinal pigment epithelium (RPE)-choroid complex was evaluated by DNA microarray and real-time RT-PCR analyses 3 days after laser treatment. HA synthesis and CD44 expression were examined by immunohistochemistry 1 week after photocoagulation. Mice with laser-induced CNV were systemically administered the HA synthesis inhibitor 4-methylumbelliferone (MU) or an anti- CD44-neutralizing antibody. The response of CNV was analyzed by volumetric measurements 1 week after photocoagulation. Macrophage infiltration into CNV lesions was evaluated by real-time RT-PCR for F4/80 3 days after laser-induced injury. RESULTS. The induction of CNV led to a significant increase in expression of CD44 and HAS2 mRNA. HA and CD44 were immunopositive in the CNV lesions. Compared with vehicle treatment, the systemic application of MU significantly attenuated CNV volume in a dose-dependent fashion, together with macrophage infiltration into the lesions. Consistently, antibody- based blockade of CD44 resulted in a significant reduction of CNV volume, compared with the isotype control. In contrast, genetic ablation of CD44 significantly augmented CNV formation together with HA accumulation and macrophage infiltration, compared with wild-type mice. CONCLUSIONS. These results indicate a significant role of HA and its receptor CD44 in the development of CNV. (Invest Ophthalmol Vis Sci.

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An essential role of the aPKC-Aurora A-NDEL1 pathway in neurite elongation by modulation of microtubule dynamics

Mori Daisuke, Yamada Masami, Mimori-Kiyosue Yuko, Shirai Yasuhito, Suzuki Atsushi, Ohno Shigeo, Saya Hideaki, Wynshaw-Boris Anthony, Hirotsune Shinji

Nature Cell Biology 11 ( 9 ) 1057 - 1068 2009

ISSN 1465-7392

Orchestrated remodelling of the cytoskeketon is prominent during neurite extension. In contrast with the extensive characterization of actin filament regulation, little is known about the dynamics of microtubules during neurite extension. Here we identify an atypical protein kinase C (aPKC)-Aurora A-NDEL1 pathway that is crucial for the regulation of microtubule organization during neurite extension. aPKC phosphorylates Aurora A at Thr 287 (T287), which augments interaction with TPX2 and facilitates activation of Aurora A at the neurite hillock, followed by phosphorylation of NDEL1 at S251 and recruitment. Suppression of aPKC, Aurora A or TPX2, or disruption of Ndel1, results in severe impairment of neurite extension. Analysis of microtubule dynamics with a microtubule plus-end marker revealed that suppression of the aPKC-Aurora A-NDEL1 pathway resulted in a significant decrease in the frequency of microtubule emanation from the microtubule organizing centre (MTOC), suggesting that Aurora A acts downstream of aPKC. These findings demonstrate a surprising role of aPKC-Aurora A-NDEL1 pathway in microtubule remodelling during neurite extension.

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p53 regulates toll-like receptor 3 expression and function in human epithelial cell lines

Taura Manabu, Eguma Ayaka, Suico Mary Ann, Shuto Tsuyoshi, Koga Tomoaki, Komatsu Kensei, Komune Takefumi, Sato Takashi, Saya Hideyuki, Li Jian Dong, Kai Hirofumi

Molecular and Cellular Biology 28 ( 21 ) 6557 - 6567 2008.11

ISSN 0270-7306

Toll-like receptors (TLRs) are important sensors of microbial pathogens and mediators of innate immune responses. Although the signal transduction of TLRs is well elucidated, their basal regulation is largely unexplored. Here we show that the tumor suppressor p53 positively regulates the transcription of TLR3, a receptor for viral double-stranded RNA and poly(I-C), by binding to the p53 site in the TLR3 promoter. TLR3 expression was lower in HCT116 p53^-/- cells than in HCT116 p53^+/+ cells. Activation of p53 by 5-fluorouracil increased the TLR3 mRNA in epithelial cell lines with wild-type p53 but not in cell lines harboring mutant p53. Knockdown of p53 by small interfering RNA decreased the TLR3 expression. TLR3 mRNA was also lower in liver and intestine of p53^-/- mice than in p53^-/- mice. Furthermore, the poly(I-C)-induced phosphorylation of IκB-α, nuclear translocation of NF-κB, and phosphorylation of interferon regulatory transcription factor 3, were drastically reduced in HCT116 p53^-/- cells, indicating a dysregulation of the two signaling pathways governed by TLR3. Consequently, induction of interleukin-8 and beta interferon after poly(I-C) stimulation was impaired in HCT116 p53^-/- cells. These results suggest that p53 influences TLR3 expression and function and highlight a role of p53 in innate immune response in epithelial cells.

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An evolutionarily conserved leucine-rich repeat protein CLERC is a centrosomal protein required for spindle pole integrity

Muto Yoshinori, Yoshioka Takashi, Kimura Masashi, Matsunami Miki, Saya Hideyuki, Okano Yukio

Cell Cycle 7 ( 17 ) 2738 - 2748 2008.09

ISSN 1538-4101

The centrosome functions as the microtubule-organizing center (MTOC) and plays a vital role in organizing spindle poles during mitosis. The pair of centrioles, which are the core components of the centrosome, duplicate once per cell cycle, and this feature is essential for the establishment of spindle bipolarity. Here we describe the molecular characterization of a novel protein called CLERC (Centrosomal leucine-rich repeat and coiled-coil containing protein) which is a human ortholog of Chlamydomonas Vfl1 protein. CLERC is a protein of 1032 amino acids with a calculated molecular mass of 120 kDa and possesses leucine-rich repeat and coiled-coil domains. Database searches revealed that CLERC has homologs in a wide variety of eukaryotes and is evolutionarily conserved. Endogenous CLERC protein associated with the centrosomes throughout the cell cycle and accumulated during mitosis. RNAi-mediated depletion of CLERC blocked formation of normal mitotic spindles and led to multipolar spindles. Moreover, many of the spindle poles in CLERC depleted cells contained only one centriole, indicating that centrosomes split into fractions containing a single centriole. These data indicate that the major function of CLERC during mitosis is to maintain the structural integrity of centrosomes, thereby contributing to spindle bipolarity.

Role of CD44-mediated signal in cancer invasion and metastasis

Saya Hideyuki, Nagano Osamu

Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme 53 ( 10 ) 1225 - 1230 2008.08

ISSN 0039-9450

AIP regulates stability of Aurora-A at early mitotic phase coordinately with GSK-3β

Fumoto K., Lee P. C., Saya H., Kikuchi A.

Oncogene 27 ( 32 ) 4478 - 4487 2008.07

ISSN 0950-9232

Glycogen synthase kinase-3 (GSK-3β) regulates microtubule dynamics and cellular polarity through phosphorylating various microtubule associating proteins and plus-end tracking proteins. Although it was also reported that GSK-3β is inactivated by protein kinase B at the spindle poles, functions and targets of GSK-3β in the mitotic phase are unknown. Here, we identified Aurora-A-interacting protein (AIP), a negative regulator of Aurora-A, as a binding partner of GSK-3β. AIP was colocalized with Aurora-A and GSK-3β to the spindle poles in metaphase, and its depletion in cells stabilized and activated Aurora-A in early mitotic phase and caused mitotic cell arrest. Treatment of the cells with a GSK-3β inhibitor reduced the protein level of Aurora-A and this reduction was suppressed by AIP knockdown. AIP was phosphorylated by GSK-3β, and an AIP mutant in which the GSK-3β phosphorylation site was mutated could bind and downregulate Aurora-A more efficiently. These results suggest that GSK-3β modulates the early mitotic Aurora-A level through binding and phosphorylating AIP.

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