Details of a Researcher - Saya, Hideyuki

Papers - Saya, Hideyuki

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Aurora A overexpression induces cellular senescence in mammary gland hyperplastic tumors developed in p53-deficient mice

Zhang D., Shimizu T., Araki N., Hirota T., Yoshie M., Ogawa K., Nakagata N., Takeya M., Saya H.

Oncogene 27 ( 31 ) 4305 - 4314 2008.07

ISSN 0950-9232

Aurora A mitotic kinase is frequently overexpressed in various human cancers and is widely considered to be an oncoprotein. However, the cellular contexts in which Aurora A induces malignancy in vivo are still unclear. We previously reported a mouse model in which overexpression of human Aurora A in the mammary gland leads to small hyperplastic changes but not malignancy because of the induction of p53-dependent apoptosis. To study the additional factors required for Aurora A-associated tumorigenesis, we generated a new Aurora A overexpression mouse model that lacks p53. We present evidence here that Aurora A overexpression in primary mouse embryonic fibroblasts (MEFs) that lack p53 overrides postmitotic checkpoint and leads to the formation of multinucleated polyploid cells. Induction of Aurora A overexpression in the mammary glands of p53-deficient mice resulted in development of precancerous lesions that were histologically similar to atypical ductal hyperplasia in human mammary tissue and showed increased cellular senescence and p16 expression. We further observed DNA damage in p53-deficient primary MEFs after Aurora A overexpression. Our results suggest that Aurora A overexpression in mammary glands is insufficient for the development of malignant tumors in p53-deficient mice because of the induction of cellular senescence. Both p53 and p16 are critical in preventing mammary gland tumorigenesis in the Aurora A overexpression mouse model.

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Rb depletion results in deregulation of E-cadherin and induction of cellular phenotypic changes that are characteristic of the epithelial-to- mesenchymal transition

Arima Yoshimi, Inoue Yasumichi, Shibata Tatsuhiro, Hayashi Hidemi, Nagano Osamu, Saya Hideyuki, Taya Yoichi

Cancer Research 68 ( 13 ) 5104 - 5112 2008.07

ISSN 0008-5472

The retinoblastoma tumor suppressor protein (Rb) is mutated or expressed at very low levels in several tumor types, including retinoblastoma and osteosarcoma, as well as small cell lung, colon, prostate, bladder, and breast carcinomas. Loss or reduction of Rb expression is seen most commonly in high-grade breast adenocarcinomas, suggesting that a relationship may exist between loss of Rb function and a less-differentiated state, increased proliferation, and high metastatic potential. In this study, we found that knockdown of Rb by small interfering RNA in MCF7 breast cancer cells disrupts cell-cell adhesion and induces a mesenchymal-like phenotype. The epithelial-to-mesenchymal transition (EMT), a key event in embryonic morphogenesis, is implicated in the metastasis of primary tumors. Additionally, Rb is decreased during growth factor- and cytokine-induced EMT and overexpression of Rb inhibits the EMT in MCF10A human mammary epithelial cells. Ectopic expression and knockdown of Rb resulted in increased or reduced expression of E-cadherin, which is specifically involved in epithelial cell-cell adhesion. Other EMT-related transcriptional factors, including Slug and Zeb-1, are also induced by Rb depletion. Furthermore, we confirmed that Rb binds to an E-cadherin promoter sequence in association with the transcription factor activator protein-2A. Finally, in breast cancer specimens, we observed a concurrent downregulation of Rb and E-cadherin expression in mesenchymal-like invasive cancers. These findings suggest that Rb inactivation contributes to tumor progression due to not only loss of cell proliferation control but also conversion to an invasive phenotype and that the inhibition of EMT is a novel tumor suppressor function of Rb.

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The ERK-RSK1 activation by growth factors at G2 phase delays cell cycle progression and reduces mitotic aberrations

Nam Hyun Ja, Kim Sujeong, Lee Min Woo, Lee Bok Soon, Hara Toshihiro, Saya Hideyuki, Cho Hyeseong, Lee Jae Ho

Cellular Signalling 20 ( 7 ) 1349 - 1358 2008.07

ISSN 0898-6568

Growth factors accelerate G0 to S progression in the cell cycle, however, the roles of growth factors in other cell cycle phases are largely unknown. Here, we show that treatment of HeLa cells with hepatocyte growth factor (HGF) at G2 phase induced the G2/M transition delay as evidenced by FACS analysis as well as by mitotic index and time-lapse analyses. Growth factors such as epidermal growth factor (EGF) and fibroblast growth factor (FGF) also induced G2/M transition delay like HGF. HGF treatment at G2 phase causes a delayed activation of cyclin B1-associated kinase and a diminished nuclear translocation of cyclin B1. Either U0126, a MAPK kinase (MEK) inhibitor, or kinase-dead mutant of ribosomal S6 kinase (RSK) abolished the delay. Additionally, knockdown of RSK1, but not RSK2, with siRNA abrogated the delay, indicating that the extracellular-regulated protein kinase (ERK)-RSK1 mediates the HGF-induced delay. We further found that the delay in G2/M transition of cells expressing oncogenic HGF receptor, M1268T, was abolished by RSK1 knockdown. Intriguingly, we observed that HGF induced chromosomal segregation defects, and depletion of RSK1, but not RSK2, aggravated these chromosomal aberrations. Taken together, the ERK-RSK1 activation by growth factors delays G2/M transition and this might be required to maintain genomic integrity during growth factor stimulation.

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Activated macrophages promote Wnt signalling through tumour necrosis factor-α in gastric tumour cells

Oguma Keisuke, Oshima Hiroko, Aoki Masahiro, Uchio Ryusei, Naka Kazuhito, Nakamura Satoshi, Hirao Atsushi, Saya Hideyuki, Taketo Makoto Mark, Oshima Masanobu

EMBO Journal 27 ( 12 ) 1671 - 1681 2008.06

ISSN 0261-4189

All Rights Reserved.The activation of Wnt/β-catenin signalling has an important function in gastrointestinal tumorigenesis. It has been suggested that the promotion of Wnt/β-catenin activity beyond the threshold is important for carcinogenesis. We herein investigated the role of macrophages in the promotion of Wnt/β-catenin activity in gastric tumorigenesis. We found β-catenin nuclear accumulation in macrophage-infiltrated dysplastic mucosa of the K19-Wnt1 mouse stomach. Moreover, macrophage depletion in Apc ^Δ716 mice resulted in the suppression of intestinal tumorigenesis. These results suggested the role of macrophages in the activation of Wnt/β-catenin signalling, which thus leads to tumour development. Importantly, the conditioned medium of activated macrophages promoted Wnt/β-catenin signalling in gastric cancer cells, which was suppressed by the inhibition of tumour necrosis factor (TNF)-α. Furthermore, treatment with TNF-α induced glycogen synthase kinase 3β (GSK3β) phosphorylation, which resulted in the stabilization of β-catenin. We also found that Helicobacter infection in the K19-Wnt1 mouse stomach caused mucosal macrophage infiltration and nuclear β-catenin accumulation. These results suggest that macrophage-derived TNF-α promotes Wnt/β-catenin signalling through inhibition of GSK3β, which may contribute to tumour development in the gastric mucosa.

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HBV X protein targets hBubR1, which induces dysregulation of the mitotic checkpoint

Kim S., Park S. Y., Yong H., Famulski J. K., Chae S., Lee J. H., Kang C. M., Saya H., Chan G. K., Cho H.

Oncogene 27 ( 24 ) 3457 - 3464 2008.05

ISSN 0950-9232

Accurate chromosomal segregation is monitored by the mitotic checkpoint, and an increased rate of chromosomal missegregation leads to chromosomal instability (CIN). Here, we demonstrate that the HBV X protein (HBx) binds BubR1, a component of the mitotic checkpoint complex and co-localizes with BubR1 at the kinetochores. HBx binding to BubR1 attenuates the association between BubR1 and CDC20, an activator of the anaphase-promoting complex/cyclosome (APC/C) and induces slippage of mitotic arrest in the presence of microtubule poisons. In addition, HBx binding to BubR1 results in the accumulation of lagging chromosomes and chromosome bridges. In contrast, a C-terminally truncated HBx mutant (HBx^1-100) fails to bind BubR1 and does not cause aberrant chromosomal segregation. This provides a novel mechanism for dysregulation of the mitotic checkpoint by a viral pathogen linking it to the accumulation of chromosomal instability in HBV-associated hepatocarcinogenesis.

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EGFR and ErbB2 are functionally coupled to CD44 and regulate shedding, internalization and motogenic effect of CD44

Pályi-Krekk Zsuzsanna, Barok Márk, Kovács Tamás, Saya Hideyuki, Nagano Osamu, Szöllosi János, Nagy Peter

Cancer Letters 263 ( 2 ) 231 - 242 2008.05

ISSN 0304-3835

Activation of the ErbB family of receptor tyrosine kinases is involved in a range of human cancers. Transmembrane signaling mediated by ErbB proteins is stimulated by peptide growth factors and is blocked by monoclonal antibodies such as trastuzumab and pertuzumab. ErbB receptors exert their function in conjunction with non-ErbB proteins, e.g. CD44. Here we show that epidermal growth factor (EGF) and heregulin induce CD44 shedding in JIMT-1, an ErbB2-overexpressing cell line resistant to trastuzumab, accompanied by internalization and intramembrane proteolysis of CD44 and enhanced cellular motility. These effects of EGF and heregulin are blocked by pertuzumab. Trastuzumab inhibits the heregulin- and hyaluronan oligosaccharide-induced shedding and internalization of CD44 and their motogenic effect. Trastuzumab also blocks CD44 shedding from JIMT-1 xenograft tumors in vivo. At the same time the internalization rate of trastuzumab is increased by hyaluronan oligosaccharide treatment in vitro. Our experiments point to an unexpected, but potentially important mechanism of action of ErbB receptor-targeted monoclonal antibodies used in the treatment of cancer.

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Neurofibromatosis type 1 (NF1) tumor suppressor, neurofibromin, regulates the neuronal differentiation of PC12 cells via its associating protein, CRMP-2

Patrakitkomjorn Siriporn, Kobayashi Daiki, Morikawa Takashi, Wilson Masayo Morifuji, Tsubota Nobuyuki, Irie Atsushi, Ozawa Tatsuya, Aoki Masashi, Arimura Nariko, Kaibuchi Kozo, Saya Hideyuki, Araki Norie

Journal of Biological Chemistry 283 ( 14 ) 9399 - 9413 2008.04

ISSN 0021-9258

Neurofibromatosis type 1 (NF1) tumor suppressor gene product, neurofibromin, functions in part as a Ras-GAP, a negative regulator of Ras. Neurofibromin is implicated in the neuronal abnormality of NF1 patients; however, the precise cellular function of neurofibromin has yet to be clarified. Using proteomic strategies, we identified a set of neurofibromin-associating cellular proteins, including axon regulator CRMP-2 (Collapsin response mediator protein-2). CRMP-2 directly bound to the C-terminal domain of neurofibromin, and this association was regulated by the manner of CRMP-2 phosphorylation. In nerve growth factor-stimulated PC12 cells, neurofibromin and CRMP-2 co-localized particularly on the distal tips and branches of extended neurites. Suppression of neurofibromin using NF1 small interfering RNA significantly inhibited this neurite outgrowth and up-regulated a series of CRMP-2 phosphorylations by kinases identified as CDK5, GSK-3b, and Rho kinase. Overexpression of the NF1-RAS-GAP-related domain rescued these NF1 small interfering RNA-induced events. Our results suggest that neurofibromin regulates neuronal differentiation by performing one or more complementary roles. First, neurofibromin directly regulates CRMP-2 phosphorylation accessibility through the complex formation. Also, neurofibromin appears to indirectly regulate CRMP-2 activity by suppressing CRMP-2-phosphorylating kinase cascades via its Ras-GAP function. Our study demonstrates that the functional association of neurofibromin and CRMP-2 is essential for neuronal cell differentiation and that lack of expression or abnormal regulation of neurofibromin can result in impaired function of neuronal cells, which is likely a factor in NF1-related pathogenesis.

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Visualizing the dynamics of p21^Waf1/Cip1 cyclin-dependent kinase inhibitor expression in living animals

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

Proceedings of the National Academy of Sciences of the United States of America 104 ( 38 ) 15034 - 15039 2007.09

ISSN 0027-8424

Although the role of p21^Waf1/Cip1 gene expression is well documented in various cell culture studies, its in vivo roles are poorly understood. To gain further insight into the role of p21^Waf1/Cip1 gene expression in vivo, we attempted to visualize the dynamics of p21 ^Waf1/Cip1 gene expression in living animals. In this study, we established a transgenic mice line (p21-p-luc) expressing the firefly luciferase under the control of the p21^Waf1/Cip1 gene promoter. In conjunction with a noninvasive bioluminescent imaging technique, p21-p-luc mice enabled us to monitor the endogenous p21^Waf1/Cip1 gene expression in vivo. By monitoring and quantifying the p21^Waf1/Cip1 gene expression repeatedly in the same mouse throughout its entire lifespan, we were able to unveil the dynamics of p21^Waf1/Cip1 gene expression in the aging process. We also applied this system to chemically induced skin carcinogenesis and found that the levels of p21^Waf1/Cip1 gene expression rise dramatically in benign skin papillomas, suggesting that p21^Waf1/Cip1 plays a preventative role(s) in skin tumor formation. Surprisingly, moreover, we found that the level of p21^Waf1/Cip1 expression strikingly increased in the hair bulb and oscillated with a 3-week period correlating with hair follicle cycle progression. Notably, this was accompanied by the expression of p63 but not p53. This approach, together with the analysis of p21 ^Waf1/Cip1 knockout mice, has uncovered a novel role for the p21 ^Waf1/Cip1 gene in hair development. These data illustrate the unique utility of bioluminescence imaging in advancing our understanding of the timing and, hence, likely roles of specific gene expression in higher eukaryotes.

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The UHRF family

Bronner Christian, Achour Mayada, Arima Yoshimi, Chataigneau Thierry, Saya Hideyuki, Schini-Kerth Valérie B.

Pharmacology and Therapeutics 115 ( 3 ) 419 - 434 2007.09

ISSN 0163-7258

In this paper, we review the current literature about the UHRF family that in particular includes the UHRF1 and UHRF2 genes. Its members play a fundamental role in cell proliferation through different structural domains. These domains include a ubiquitin-like domain (NIRF_N), a plant homeodomain (PHD) domain, a SRA domain and a RING domain. The SRA domain has only been observed in this family probably conferring unique properties to it. The unique enzymatic activity so far identified in this family involves the RING finger that contains a ubiquitin E3 ligase activity toward, for instance, histones. The physiological roles played by the UHRF family are most likely exerted during embryogenic development and when proliferation is required in adults. Interestingly, UHRF members are putative oncogenes regulated by tumor suppressor genes, but they exert also a feedback control on these latter. Finally, we propose some new roles for this family, including regulation and/or inheritance of the epigenetic code. Alteration of these regulatory mechanisms, such as those occurring in cancer cells, may be involved in carcinogenesis. The reasons why the UHRF family could be an interesting target for developing anticancer drugs is also developed.

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Differential levels of human leukocyte antigen-class I, multidrug-resistance 1 and androgen receptor expressions in untreated prostate cancer cells

Homma Shigenori, Komohara Yoshihiro, Harada Mamoru, Saya Hideyuki, Todo Satoru, Itoh Kyogo, Noguchi Masanori

Oncology Reports 18 ( 2 ) 343 - 346 2007.08

ISSN 1021-335X

Tumors are highly robust and maintain their proliferative potential against a wide range of both host-defense mechanisms and anticancer therapies. One of the approaches to overcome cancer robustness could be combined therapy in which each modality imposes independent selective pressures against the acquired mutation of cancer. To develop such a therapy, it is crucial to understand the magnitude of acquired mutations. In this study, we investigated the levels of human leukocyte antigen (HLA)-class I, multidrug-resistance 1 (MDR1), and androgen receptor (AR) expressions in untreated prostate cancers harvested by radical prostatectomy. The mean percentages of cancer cells expressing HLA-class I, MDR and AR among the 10 cancer samples were 41, 35 and 74%, respectively. In addition, double-staining of HLA and MDR revealed the four definite populations (HLA⁺/MDR⁺, HLA+/MDR^-, HLA-/MDR⁺and HLA^-/MDR^-) in cancer tissues from the majority of cancer patients tested, and the mean percentages of cells expressing these combinations were 13, 29, 22 and 38%, respectively. Similar results were obtained by double-staining of HLA and AR, except for 2 cases in which HLA ^-/AR⁺cancer cells predominated. These results indicated that untreated prostate cancer cells acquired a wide range of genomic mutations, which may have been caused by internal host pressure to eliminate malignant cells, and would provide evidence of the robustness of untreated prostate cancer.

Zoledronate-induced S phase arrest and apoptosis accompanied by DNA damage and activation of the ATM/Chk1/cdc25 pathway in human osteosarcoma cells

Iguchi Toyotaka, Miyakawa Yoshitaka, Saito Kaori, Nakabayashi Chika, Nakanishi Makoto, Saya Hideyuki, Ikeda Yasuo, Kizaki Masahiro

International Journal of Oncology 31 ( 2 ) 285 - 291 2007.08

ISSN 1019-6439

Osteosarcoma is one of the most common primary malignant tumors of the bone in children and adolescents. Some patients continue to have a poor prognosis, as they have metastatic disease and frequent occurrence of drug resistance. Zoledronate is a nitrogen-containing bisphosphonate that has been used for the treatment of hypercalcemia and bone metastasis, because it induces apoptosis in osteoclasts and tumor cells by inhibiting the isoprenylation of intracellular small G proteins. Besides inhibiting isoprenylation, little is known about the manner by which bisphosphonates inhibit cellular proliferation and induce apoptosis. This prompted us to investigate the inhibitory effects of zoledronate in human osteosarcoma cell lines, HOS and MG63. HOS cells accumulated in S phase around 6 h after treatment with 10 μM zoledronate, followed by apoptosis. When HOS cells were treated with zoledronate, ATM kinase and its substrate, check-point kinase (Chk)1, were phosphorylated. Zoledronate also induced phosphorylation of cdc25a (Thr506) in HOS cells, which is a substrate of Chk1, and its phosphorylation is known to be critical for S phase arrest. Following treatment with zoledronate, phosphorylated histone H2AX (γ-H2AX) displayed patterns of nuclear foci in HOS cells. As γ-H2AX accumulates at dsDNA breaks, these results demonstrate that zoledronate induced DNA damage and S phase arrest, accompanied by activation of the ATM/Chk1/cdc25 pathway in a human osteosarcoma cell line.

Serine protease Omi/HtrA2 targets WARTS kinase to control cell proliferation

Kuninaka S., Iida S. I., Hara T., Nomura M., Naoe H., Morisaki T., Nitta M., Arima Y., Mimori T., Yonehara S., Saya H.

Oncogene 26 ( 17 ) 2395 - 2406 2007.04

ISSN 0950-9232

The serine protease Omi/HtrA2 was initially regarded as a proapoptotic molecule that proteolyses several proteins to induce cell death. Recent studies, however, indicate that loss of Omi protease activity increases susceptibility to stress-induced cell death. These complicated findings suggest that the protease activity of Omi is involved not only in apoptosis but also in cellular homeostasis. However, the targets which Omi uses to mediate this novel process are unknown. Previously, we showed that WARTS (WTS)/large tumor-suppressor 1 mitotic kinase interacts with the protein/discs-large protein/zonula (PDZ) domain of Omi and promotes its protease activity. We now report that WTS is a substrate for Omi protease activity, thus it is not only a regulator but also a downstream target of this protease. Interaction with Omi PDZ domain is required for WTS to be proteolysed. When caspase-9-deficient mouse embryonic fibroblasts (MEFs) were treated with staurosporine, WTS was proteolysed by activated endogenous Omi without induction of cell death. Therefore, protease activity of Omi and proteolysis of WTS are not necessarily required for cell death. We found that depletion of Omi from HeLa cells results in accelerated cell proliferation despite no significant change in the duration of mitosis. The depletion of WTS showed the same effect on S phase progression. Therefore, WTS proteolytic fragment(s) generated by Omi may act as an inhibitor of G1/S progression. Our data reveal a role for Omi-mediated processing of WTS in negative regulation of cell cycle progression at interphase, suggesting a novel function of Omi other than apoptosis.

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ADAM-17 associated with CD44 cleavage and metastasis in oral squamous cell carcinoma

Takamune Yasuo, Ikebe Tetsuro, Nagano Osamu, Nakayama Hideki, Ota Kazutoshi, Obayashi Takehisa, Saya Hideyuki, Shinohara Masanori

Virchows Archiv 450 ( 2 ) 169 - 177 2007.02

ISSN 0945-6317

ADAM-17 (a disintegrin and metalloproteinase 17) is a membrane-anchored protein, which can cleave the ectodomain in a variety of transmembrane proteins. In the in vitro experiments with tumor cells, ADAM-17 is reported to cleave CD44, an adhesion molecule that interacts with hyaluronic acid, to promote tumor cell migration. In the present study, we examined ADAM-17 expression and CD44 cleavage in specimens from 50 patients diagnosed to have oral squamous cell carcinoma (SCC). Each specimen was divided into two pieces, one was studied by immunohistochemistry and the other was subjected to a Western blot. By coordinating the results of both analyses, ADAM-17 expression was evaluated to be high in 23 cases (46%). When CD44 cleavage was also studied by immunohistochemical staining as well as with Western blotting, CD44 cleavage was judged to be positive in 29 cases (58%). When the ADAM-17 expression level was compared with the CD44 cleavage state, most of the cases expressing high levels of ADAM-17 (87%) showed positive CD44 cleavage. The level of ADAM-17 expression was significantly correlated to the nodal metastasis and local recurrence in oral SCC. Our findings suggest that ADAM-17 is involved in CD44 cleavage and contributes to tumor progression in oral SCC.

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NDEL1 phosphorylation by Aurora-A kinase is essential for centrosomal maturation, separation, and TACC3 recruitment

Mori Daisuke, Yano Yoshihisa, Toyo-Oka Kazuhito, Yoshida Noriyuki, Yamada Masami, Muramatsu Masami, Zhang Dongwei, Saya Hideyuki, Toyoshima Yoko Y., Kinoshita Kazuhisa, Wynshaw-Boris Anthony, Hirotsune Shinji

Molecular and Cellular Biology 27 ( 1 ) 352 - 367 2007.01

ISSN 0270-7306

NDEL1 is a binding partner of LIS1 that participates in the regulation of cytoplasmic dynein function and microtubule organization during mitotic cell division and neuronal migration. NDEL1 preferentially localizes to the centrosome and is a likely target for cell cycle-activated kinases, including CDK1. In particular, NDEL1 phosphorylation by CDK1 facilitates katanin p60 recruitment to the centrosome and triggers microtubule remodeling. Here, we show that Aurora-A phosphorylates NDEL1 at Ser251 at the beginning of mitotic entry. Interestingly, NDEL1 phosphorylated by Aurora-A was rapidly downregulated thereafter by ubiquitination-mediated protein degradation. In addition, NDEL1 is required for centrosome targeting of TACC3 through the interaction with TACC3. The expression of Aurora-A phosphorylation-mimetic mutants of NDEL1 efficiently rescued the defects of centrosomal maturation and separation which are characteristic of Aurora-A-depleted cells. Our findings suggest that Aurora-A-mediated phosphorylation of NDEL1 is essential for centrosomal separation and centrosomal maturation and for mitotic entry.

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Expression of WT1 protein and correlation with cellular proliferation in glial tumors

Saya Hideyuki

Neurologia Medico-Chirurgica 47 ( 4 ) 170 2007

ISSN 0470-8105

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Aurora kinases

Saya Hideyuki

Seikagaku 79 ( 2 ) 131 - 139 2007

ISSN 0037-1017

Mitogenic signalling and the p16^INK4a-Rb pathway cooperate to enforce irreversible cellular senescence

Takahashi Akiko, Ohtani Naoko, Yamakoshi Kimi, Iida Shin Ichi, Tahara Hidetoshi, Nakayama Keiko, Nakayama Keiichi I., Ide Toshinori, Saya Hideyuki, Hara Eiji

Nature Cell Biology 8 ( 11 ) 1291 - 1297 2006.11

ISSN 1465-7392

The p16^INK4a cyclin-dependent kinase inhibitor has a key role in establishing stable G1 cell-cycle arrest through activating the retinoblastoma (Rb) tumour suppressor protein pRb^1-5 in cellular senescence. Here, we show that the p16^INK4a/ Rb-pathway also cooperates with mitogenic signals to induce elevated intracellular levels of reactive oxygen species (ROS), thereby activating protein kinase Cδ (PKCδ) in human senescent cells. Importantly, once activated by ROS, PKCδ promotes further generation of ROS, thus establishing a positive feedback loop to sustain ROS-PKCδ signalling^6-8. Sustained activation of ROS-PKCδ signalling irreversibly blocks cytokinesis, at least partly through reducing the level of WARTS (also known as LATS1), a mitotic exit network (MEN) kinase required for cytokinesis^9-11, in human senescent cells. This irreversible cytokinetic block is likely to act as a second barrier to cellular immortalization ensuring stable cell-cycle arrest in human senescent cells. These results uncover an unexpected role for the p16^INK4a-Rb pathway and provide a new insight into how senescent cell-cycle arrest is enforced in human cells.

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Molecular mechanisms of anti-cancer therapies

Saya Hideyuki

Japanese Journal of Neurosurgery 15 ( 10 ) 688 - 693 2006.10

ISSN 0917-950X

Cell cycle checkpoints block the transition from one phase of the cell cycle to the next phase until all processes are completed. Defects in these checkpoint functions lead to genomic instability, which results in the development of malignant tumors. However, it has become known that a loss of checkpoint function is directly related to sensitivity to antineoplastic treatments. Most cancer cells are deficient in G1 checkpoint function and therefore fail to arrest in the G1 phase on exposure to genotoxic agents. Instead, they accumulate temporarily in the G2 phase. However, given that the G2 checkpoint is also partially impaired in cancer cells, they are unable to maintain G2 arrest and eventually die as they enter mitosis. This process is known as mitotic catastrophe or mitotic death. Mitotic catastrophe is an important mechanism for the induction of cell death in cancer cells by antineoplastic agents. Cells entering mitosis with DNA damage arrest at metaphase for more than 10hr without chromosome segregation and subsequently die directly from metaphase. This long-term metaphase arrest before catastrophic death is termed the "precatastrophic phase". We found that spindle check is activated during the precatastrophic phase. Therefore, inhibition of the spindle checkpoint function as a result of depletion of BubR1 or Mad2 by RNAi caused cells to escape from mitotic catastrophe and led to subsequent abnormal mitosis when DNA damage is induced. Our data suggest that a dysfunction of the mitotic checkpoint in cancer cells may confer resistance to DNA-damaging agents and malignant progression. In this review article, I would like to summarize how cancer cells are terminated by DNA-damaging agents and anti-mitotic drugs. Based on these findings, I would like to propose the novel mechanisms by which tumors become insensitive to those chemotherapeutic agents.

Centrosome amplification in adult T-cell leukemia and human T-cell leukemia virus type 1 Tax-induced human T cells

Nitta Takayuki, Kanai Masayuki, Sugihara Eiji, Tanaka Masakazu, Sun Binilian, Nagasawa Toshiro, Sonoda Shunro, Saya Hideyuki, Miwa Masanao

Cancer Science 97 ( 9 ) 836 - 841 2006.09

ISSN 1347-9032

Centrosomes play pivotal roles in cell polarity, regulation of the cell cycle and chromosomal segregation. Centrosome amplification was recently described as a possible cause of aneuploidy in certain solid tumors and leukemias. ATL is a T-cell malignancy caused by HTLV-1. Although the precise mechanism of cell transformation is unclear, the HTLV-1-encoded protein, Tax, is thought to play a crucial role in leukemogenesis. Here we demonstrate that lymphocytes isolated from patients with ATL show centrosome amplification and that a human T cell line shows centrosome amplification after induction of Tax, which was suppressed by CDK inhibitors. Micronuclei formation was also observed after centrosome amplification in Tax-induced human T cells. These findings suggest that Tax deregulates CDK activity and induces centrosome amplification, which might be associated with cellular transformation by HTLV-1 and chromosomal instability in HTLV-1-infected human T cells.

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Dynamics of mitotic spindle

Kinoshita Kazuhisa, Saya Hideyuki

Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme. 51 ( 6 Suppl ) 761 - 766 2006.05

ISSN 0039-9450

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