Kyushu University Academic Staff Educational and Research Activities Database
List of Papers
Keiichi Nakayama Last modified date:2018.06.13

Professor / Department of Molecular and Cellular Biology / Medical Institute of Bioregulation

1. Yutaka Hashimoto, Michiko Shirane, Keiichi Nakayama, TMEM55B contributes to lysosomal homeostasis and amino acid-induced mTORC1 activation, Genes to Cells,, 2018.01, Mammalian/mechanistic target of rapamycin complex 1 (mTORC1) responds to growth factors and nutrient availability. Amino acids induce the recruitment of mTORC1 to the lysosomal membrane and its consequent activation, but the molecular mechanism of such activation has remained unclear. We have now examined the role of TMEM55B, a lysosomal protein of unknown molecular function, in this process on the basis of the results of proteomics and immunofluorescence analyses showing that TMEM55B interacts with many proteins that participate in mTORC1 activation including components of the vacuolar-type proton ATPase (V-ATPase) and Ragulator complexes at the lysosomal membrane. The amino acid-induced phosphorylation of the mTORC1 substrates S6K and 4E-BP was attenuated in TMEM55B-depleted cells compared with control cells. Depletion of TMEM55B was also found to evoke lysosomal stress as showed by translocation of the transcription factor TFEB to the nucleus. Furthermore, recruitment of the V1 domain subcomplex of V-ATPase to lipid rafts was abrogated in TMEM55B-depleted cells. Collectively, our results suggest that TMEM55B contributes to assembly of the V-ATPase complex in lipid rafts of the lysosomal membrane and to subsequent activation of mTORC1..
2. Akinobu Matsumoto, Keiichi Nakayama, Hidden peptides encoded by putative noncoding RNAs, Cell Structure and Function,, 43, 1, 75-83, 2018.01, Although the definition of a noncoding RNA (ncRNA) is an RNA molecule that does not encode a protein, recent evidence has revealed that some ncRNAs are indeed translated to give rise to small polypeptides (usually containing fewer than 100 amino acids). Despite their small size, however, these peptides are often biologically relevant in that they are required for a variety of cellular processes. In this review, we summarize the production and functions of peptides that have been recently identified as translation products of putative ncRNAs..
3. Shogo Nakayama, Kanae Yumimoto, Atsuki Kawamura, Keiichi Nakayama, Degradation of the endoplasmic reticulum–anchored transcription factor MyRF by the ubiquitin ligase SCFFbxw7 in a manner dependent on the kinase GSK-3, Journal of Biological Chemistry,, 293, 15, 5705-5714, 2018.01, The ubiquitin-proteasome system regulates the abundance of many cellular proteins by mediating their targeted degradation. We previously developed a method— differential proteomics–based identification of ubiquitylation substrates (DiPIUS)—for the comprehensive identification of substrates for a given F-box protein subunit of SCF-type ubiquitin ligases. We have now applied DiPIUS to the F-box protein Fbxw7 in three cell lines (mHepa, Neuro2A, and C2C12) and thereby identified myelin regulatory factor (MyRF), an endoplasmic reticulum–anchored transcription factor that is essential for myelination of nerves in the central nervous system, as a candidate substrate of Fbxw7 specifically in mHepa cells. Co-immunoprecipitation analysis confirmed that the NH2-terminal cytoplasmic domain of MyRF interacted with Fbxw7 in these cells. Furthermore, an in vitro ubiquitylation assay revealed that MyRF undergoes polyubiqui-tylation in the presence of purified recombinant SCFFbxw7. In addition, the stability of MyRF in mHepa cells was increased by mutation of a putative phosphodegron sequence or by exposure of the cells to an inhibitor of glycogen synthase kinase-3 (GSK-3). We found that MyRF mRNA is not restricted to the central nervous system but is instead distributed widely among mouse tissues. Furthermore, with the use of RNA sequencing in mHepa cells overexpressing or depleted of MyRF, we identified many novel potential target genes of MyRF. Our results thus suggest that Fbxw7 controls the transcription of MyRF target genes in various tissues through regulation of MyRF protein stability in a manner dependent on MyRF phosphorylation by GSK-3..
4. Masashi Mikamo, Kyoko Kitagawa, Satoshi Sakai, Chiharu Uchida, Tatsuya Ohhata, Koji Nishimoto, Hiroyuki Niida, Sayuri Suzuki, Keiichi Nakayama, Naoki Inui, Takafumi Suda, Masatoshi Kitagawa, Inhibiting Skp2 E3 ligase suppresses bleomycin-induced pulmonary fibrosis, International Journal of Molecular Sciences,, 19, 2, 2018.02, Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor prognosis and no curative therapies. SCF-Skp2 E3 ligase is a target for cancer therapy, but there have been no reports about Skp2 as a target for IPF. Here we demonstrate that Skp2 is a promising therapeutic target for IPF. We examined whether disrupting Skp2 suppressed pulmonary fibrosis in a bleomycin (BLM)-induced mouse model and found that pulmonary fibrosis was significantly suppressed in Skp2-deficient mice compared with controls. The pulmonary accumulation of fibrotic markers such as collagen type 1 and fibronectin in BLM-infused mice was decreased in Skp2-deficient mice. Moreover, the number of bronchoalveolar lavage fluid cells accompanied with pulmonary fibrosis was significantly diminished. Levels of the Skp2 target p27 were significantly decreased by BLM-administration in wild-type mice, but recovered in Skp2−/− mice. In vimentin-positive mesenchymal fibroblasts, the decrease of p27-positive cells and increase of Ki67-positive cells by BLM-administration was suppressed by Skp2-deficency. As these results suggested that inhibiting Skp2 might be effective for BLM-induced pulmonary fibrosis, we next performed a treatment experiment using the Skp2 inhibitor SZL-P1-41. As expected, BLM-induced pulmonary fibrosis was significantly inhibited by SZL-P1-41. Moreover, p27 levels were increased by the SZL-P1-41 treatment, suggesting p27 may be an important Skp2 target for BLM-induced pulmonary fibrosis. Our study suggests that Skp2 is a potential molecular target for human pulmonary fibrosis including IPF..
5. Hideo Hagihara, Vibeke S. Catts, Yuta Katayama, Hirotaka Shoji, Tsuyoshi Takagi, Freesia L. Huang, Akito Nakao, Yasuo Mori, Kuo Ping Huang, Shunsuke Ishii, Isabella A. Graef, Keiichi Nakayama, Cynthia Shannon Weickert, Tsuyoshi Miyakawa, Decreased Brain pH as a Shared Endophenotype of Psychiatric Disorders, Neuropsychopharmacology,, 43, 3, 459-468, 2018.02, Although the brains of patients with schizophrenia and bipolar disorder exhibit decreased brain pH relative to those of healthy controls upon postmortem examination, it remains controversial whether this finding reflects a primary feature of the diseases or is a result of confounding factors such as medication and agonal state. To date, systematic investigation of brain pH has not been undertaken using animal models that can be studied without confounds inherent in human studies. In the present study, we first reevaluated the pH of the postmortem brains of patients with schizophrenia and bipolar disorder by conducting a meta-analysis of existing data sets from 10 studies. We then measured pH, lactate levels, and related metabolite levels in brain homogenates from five neurodevelopmental mouse models of psychiatric disorders, including schizophrenia, bipolar disorder, and autism spectrum disorder. All mice were drug naive with the same agonal state, postmortem interval, and age within each strain. Our meta-analysis revealed that brain pH was significantly lower in patients with schizophrenia and bipolar disorder than in control participants, even when a few potential confounding factors (postmortem interval, age, and history of antipsychotic use) were considered. In animal experiments, we observed significantly lower pH and higher lactate levels in the brains of model mice relative to controls, as well as a significant negative correlation between pH and lactate levels. Our findings suggest that lower pH associated with increased lactate levels is not a mere artifact, but rather implicated in the underlying pathophysiology of schizophrenia and bipolar disorder..
6. Mami Morita, Taku Sato, Miyuki Nomura, Yoshimi Sakamoto, Yui Inoue, Ryota Tanaka, Shigemi Ito, Koreyuki Kurosawa, Kazunori Yamaguchi, Yuki Sugiura, Hiroshi Takizaki, Yoji Yamashita, Ryuichi Katakura, Ikuro Sato, Masaaki Kawai, Yoshinori Okada, Hitomi Watanabe, Gen Kondoh, Shoko Matsumoto, Ayako Kishimoto, Miki Obata, Masaki Matsumoto, Tatsuro Fukuhara, Hozumi Motohashi, Makoto Suematsu, Masaaki Komatsu, Keiichi Nakayama, Toshio Watanabe, Tomoyoshi Soga, Hiroshi Shima, Makoto Maemondo, Nobuhiro Tanuma, PKM1 Confers Metabolic Advantages and Promotes Cell-Autonomous Tumor Cell Growth, Cancer Cell,, 33, 3, 355-367.e7, 2018.03, Expression of PKM2, which diverts glucose-derived carbon from catabolic to biosynthetic pathways, is a hallmark of cancer. However, PKM2 function in tumorigenesis remains controversial. Here, we show that, when expressed rather than PKM2, the PKM isoform PKM1 exhibits a tumor-promoting function in KRASG12D-induced or carcinogen-initiated mouse models or in some human cancers. Analysis of Pkm mutant mouse lines expressing specific PKM isoforms established that PKM1 boosts tumor growth cell intrinsically. PKM1 activated glucose catabolism and stimulated autophagy/mitophagy, favoring malignancy. Importantly, we observed that pulmonary neuroendocrine tumors (NETs), including small-cell lung cancer (SCLC), express PKM1, and that PKM1 expression is required for SCLC cell proliferation. Our findings provide a rationale for targeting PKM1 therapeutically in certain cancer subtypes, including pulmonary NETs. The relative importance of PKM isoforms in tumor growth has been controversial. Morita et al. show that PKM1 promotes the growth of multiple tumor models using mouse lines expressing PKM1 or PKM2 from the endogenous Pkm locus. PKM1 is expressed in human SCLC, and it is important for SCLC cell proliferation..
7. Eri Sakai, Mizuho Nakayama, Hiroko Oshima, Yuta Kouyama, Atsushi Niida, Satoshi Fujii, Atsushi Ochiai, Keiichi Nakayama, Koshi Mimori, Yutaka Suzuki, Chang Pyo Hong, Chan Young Ock, Seong Jin Kim, Masanobu Oshima, Combined mutation of Apc, Kras, and Tgfbr2 effectively drives metastasis of intestinal cancer, Cancer Research,, 78, 5, 1334-1346, 2018.03, Colorectal cancer is driven by the accumulation of driver mutations, but the contributions of specific mutations to different steps in malignant progression are not fully understood. In this study, we generated mouse models harboring different combinations of key colorectal cancer driver mutations (Apc, Kras, Tgfbr2, Trp53, Fbxw7) in intestinal epithelial cells to comprehensively investigate their roles in the development of primary tumors and metastases. Apcδ716 mutation caused intestinal adenomas and combination with Trp53R270 mutation or Tgfbr2 deletion induced submucosal invasion. The addition of KrasG12D mutation yielded epithelial-mesenchymal transition (EMT)-like morphology and lymph vessel intravasation of the invasive tumors. In contrast, combinations of Apcδ716 with KrasG12D and Fbxw7 mutation were insufficient for submucosal invasion, but still induced EMT-like histology. Studies using tumor-derived organoids showed that KrasG12D was critical for liver metastasis following splenic transplantation, when this mutation was combined with either Apcδ716 plus Trp53R270H or Tgfbr2 deletion, with the highest incidence of metastasis displayed by tumors with a Apcδ716 KrasG12D Tgfbr2-/- genotype. RNA sequencing analysis of tumor organoids defined distinct gene expression profiles characteristic for the respective combinations of driver mutations, with upre-gulated genes in Apcδ716 KrasG12D Tgfbr2-/- tumors found to be similarly upregulated in specimens of human metastatic colorectal cancer. Our results show how activation of Wnt and Kras with suppression of TGFβ signaling in intestinal epithelial cells is sufficient for colorectal cancer metastasis, with possible implications for the development of metastasis prevention strategies..
8. Ryoichi Matsunuma, Hiroyuki Niida, Tatsuya Ohhata, Kyoko Kitagawa, Satoshi Sakai, Chiharu Uchida, Bunsyo Shiotani, Masaki Matsumoto, Keiichi Nakayama, Hiroyuki Ogura, Norihiko Shiiya, Masatoshi Kitagawa, Correction
"UV damage-induced phosphorylation of HBO1 triggers CRL4DDB2-mediated degradation to regulate cell proliferation" [Molecular and Cellular Biology 36, 3, (2016) (394-406)] doi 10.1128/MCB.00809-15, Molecular and Cellular Biology,, 38, 7, 2018.04.
9. Yasuyuki Kita, Yuta Katayama, Taichi Shiraishi, Takeru Oka, Tetsuya Sato, Mikita Suyama, Yasuyuki Ohkawa, Keishi Miyata, Yuichi Oike, Michiko Shirane, Masaaki Nishiyama, Keiichi Nakayama, The Autism-Related Protein CHD8 Cooperates with C/EBPβ to Regulate Adipogenesis, Cell Reports,, 23, 7, 1988-2000, 2018.05, The gene encoding the chromatin remodeler CHD8 is the most frequently mutated gene in individuals with autism spectrum disorder (ASD). Heterozygous mutations in CHD8 give rise to ASD that is often accompanied by macrocephaly, gastrointestinal complaints, and slender habitus. Whereas most phenotypes of CHD8 haploinsufficiency likely result from delayed neurodevelopment, the mechanism underlying slender habitus has remained unknown. Here, we show that CHD8 interacts with CCAAT/enhancer-binding protein β (C/EBPβ) and promotes its transactivation activity during adipocyte differentiation. Adipogenesis was impaired in Chd8-deleted preadipocytes, with the upregulation of C/EBPα and peroxisome-proliferator-activated receptor γ (PPARγ), two master regulators of this process, being attenuated in mutant cells. Furthermore, mice with CHD8 ablation in white preadipocytes had a markedly reduced white adipose tissue mass. Our findings reveal a mode of C/EBPβ regulation by CHD8 during adipogenesis, with CHD8 deficiency resulting in a defect in the development of white adipose tissue. Kita et al. show that autism-related protein CHD8 is essential for adipogenesis and the development of white adipose tissue. Moreover, they demonstrate that CHD8 cooperates with C/EBPβ to regulate transactivation of the genes for C/EBPα and PPARγ during adipogenesis..
10. Masaki Matsumoto, Keiichi Nakayama, The promise of targeted proteomics for quantitative network biology, Current Opinion in Biotechnology,, 54, 88-97, 2018.12, Proteomics is a powerful tool for obtaining information on a large number of proteins with regard to their expression levels, interactions with other molecules, and posttranslational modifications. Whereas nontargeted, discovery proteomics uncovers differences in the proteomic landscape under different conditions, targeted proteomics has been developed to overcome the limitations of this approach with regard to quantitation. In addition to technical advances in instruments and informatics tools, the advent of the synthetic proteome composed of synthetic peptides or recombinant proteins has advanced the adoption of targeted proteomics across a wide range of research fields. Targeted proteomics can now be applied to measurement of the dynamics of any proteins of interest under a variety of conditions as well as to estimation of the absolute abundance or stoichiometry of proteins in a given network. Multiplexed targeted proteomics assays of high reproducibility and accuracy can provide insight at the quantitative level into entire networks that govern biological phenomena or diseases. Such assays will establish a new paradigm for data-driven science..
11. Yoshiharu Muto, Masaaki Nishiyama, Akihiro Nita, Toshiro Moroishi, Keiichi Nakayama, Essential role of FBXL5-mediated cellular iron homeostasis in maintenance of hematopoietic stem cells, Nature Communications,, 8, 2017.07, Hematopoietic stem cells (HSCs) are maintained in a hypoxic niche to limit oxidative stress. Although iron elicits oxidative stress, the importance of iron homeostasis in HSCs has been unknown. Here we show that iron regulation by the F-box protein FBXL5 is required for HSC self-renewal. Conditional deletion of Fbxl5 in mouse HSCs results in cellular iron overload and a reduced cell number. Bone marrow transplantation reveals that FBXL5-deficient HSCs are unable to reconstitute the hematopoietic system of irradiated recipients as a result of stem cell exhaustion. Transcriptomic analysis shows abnormal activation of oxidative stress responses and the cell cycle in FBXL5-deficient mouse HSCs as well as downregulation of FBXL5 expression in HSCs of patients with myelodysplastic syndrome. Suppression of iron regulatory protein 2 (IRP2) accumulation in FBXL5-deficient mouse HSCs restores stem cell function, implicating IRP2 as a potential therapeutic target for human hematopoietic diseases associated with FBXL5 downregulation..
12. Hirokazu Nakatsumi, Masaki Matsumoto, Keiichi Nakayama, Noncanonical Pathway for Regulation of CCL2 Expression by an mTORC1-FOXK1 Axis Promotes Recruitment of Tumor-Associated Macrophages, Cell Reports,, 21, 9, 2471-2486, 2017.11, C-C chemokine ligand 2 (CCL2) plays pivotal roles in tumor formation, progression, and metastasis. Although CCL2 expression has been found to be dependent on the nuclear factor (NF)-κB signaling pathway, the regulation of CCL2 production in tumor cells has remained unclear. We have identified a noncanonical pathway for regulation of CCL2 production that is mediated by mammalian target of rapamycin complex 1 (mTORC1) but independent of NF-κB. Multiple phosphoproteomics approaches identified the transcription factor forkhead box K1 (FOXK1) as a downstream target of mTORC1. Activation of mTORC1 induces dephosphorylation of FOXK1, resulting in transactivation of the CCL2 gene. Inhibition of the mTORC1-FOXK1 axis attenuated insulin-induced CCL2 production as well as the accumulation of tumor-associated monocytes-macrophages and tumor progression in mice. Our results suggest that FOXK1 directly links mTORC1 signaling and CCL2 expression in a manner independent of NF-κB and that CCL2 produced by this pathway contributes to tumor progression. Nakatsumi et al. show that mTORC1 regulates CCL2 expression in a manner independent of NF-κB signaling by dephosphorylating the transcription factor FOXK1. Moreover, they demonstrate that hyperactivation of mTORC1 results in attraction of M2-type tumor-associated macrophages and promotes tumor growth in vivo via the mTORC1-FOXK1-CCL2 pathway..
13. Hidefumi Fukushima, Kouhei Shimizu, Asami Watahiki, Seira Hoshikawa, Tomoki Kosho, Daiju Oba, Seiji Sakano, Makiko Arakaki, Aya Yamada, Katsuyuki Nagashima, Koji Okabe, Satoshi Fukumoto, Eijiro Jimi, Anna Bigas, Keiichi Nakayama, Keiko Nakayama, Yoko Aoki, Wenyi Wei, Hiroyuki Inuzuka, NOTCH2 Hajdu-Cheney Mutations Escape SCFFBW7-Dependent Proteolysis to Promote Osteoporosis, Molecular Cell,, 68, 4, 645-658, 2017.11, Hajdu-Cheney syndrome (HCS), a rare autosomal disorder caused by heterozygous mutations in NOTCH2, is clinically characterized by acro-osteolysis, severe osteoporosis, short stature, neurological symptoms, cardiovascular defects, and polycystic kidneys. Recent studies identified that aberrant NOTCH2 signaling and consequent osteoclast hyperactivity are closely associated with the bone-related disorder pathogenesis, but the exact molecular mechanisms remain unclear. Here, we demonstrate that sustained osteoclast activity is largely due to accumulation of NOTCH2 carrying a truncated C terminus that escapes FBW7-mediated ubiquitination and degradation. Mice with osteoclast-specific Fbw7 ablation revealed osteoporotic phenotypes reminiscent of HCS, due to elevated Notch2 signaling. Importantly, administration of Notch inhibitors in Fbw7 conditional knockout mice alleviated progressive bone resorption. These findings highlight the molecular basis of HCS pathogenesis and provide clinical insights into potential targeted therapeutic strategies for skeletal disorders associated with the aberrant FBW7/NOTCH2 pathway as observed in patients with HCS. Fukushima et al. demonstrated that the sustained osteoclast activity in Hajdu-Cheney syndrome (HCS) is largely due to elevated protein abundance of the C terminus truncating NOTCH2 mutant that escapes FBW7-mediated ubiquitination and proteolysis, suggesting that the FBW7/NOTCH2 signaling pathway is a potential therapeutic target for osteolytic bone disorders, including HCS..
14. Ryo Yonehara, Shigeyuki Nada, Tomokazu Nakai, Masahiro Nakai, Ayaka Kitamura, Akira Ogawa, Hirokazu Nakatsumi, Keiichi Nakayama, Songling Li, Daron M. Standley, Eiki Yamashita, Atsushi Nakagawa, Masato Okada, Structural basis for the assembly of the Ragulator-Rag GTPase complex, Nature Communications,, 8, 1, 2017.12, The mechanistic target of rapamycin complex 1 (mTORC1) plays a central role in regulating cell growth and metabolism by responding to cellular nutrient conditions. The activity of mTORC1 is controlled by Rag GTPases, which are anchored to lysosomes via Ragulator, a pentameric protein complex consisting of membrane-anchored p18/LAMTOR1 and two roadblock heterodimers. Here we report the crystal structure of Ragulator in complex with the roadblock domains of RagA-C, which helps to elucidate the molecular basis for the regulation of Rag GTPases. In the structure, p18 wraps around the three pairs of roadblock heterodimers to tandemly assemble them onto lysosomes. Cellular and in vitro analyses further demonstrate that p18 is required for Ragulator-Rag GTPase assembly and amino acid-dependent activation of mTORC1. These results establish p18 as a critical organizing scaffold for the Ragulator-Rag GTPase complex, which may provide a platform for nutrient sensing on lysosomes..
15. Hiroaki Yaguchi, Ichiro Yabe, Hidehisa Takahashi, Masashi Watanabe, Taichi Nomura, Takahiro Kano, Masaki Matsumoto, Keiichi Nakayama, Masahiko Watanabe, Shigetsugu Hatakeyama, Sez6l2 regulates phosphorylation of ADD and neuritogenesis, Biochemical and Biophysical Research Communications,, 494, 1-2, 234-241, 2017.12, Increasing evidence shows that immune-mediated mechanisms may contribute to the pathogenesis of central nervous system disorders including cerebellar ataxias, as indicated by the aberrant production of neuronal surface antibodies. We previously reported a patient with cerebellar ataxia associated with production of a new anti-neuronal antibody, anti-seizure-related 6 homolog like 2 (Sez6l2). Sez6l2 is a type 1 membrane protein that is highly expressed in the hippocampus and cerebellar cortex and mice lacking Sez6l2 protein family members develop ataxia. Here we used a proteomics-based approach to show that serum derived from this patient recognizes the extracellular domain of Sez6l2 and that Sez6l2 protein binds to both adducin (ADD) and glutamate receptor 1 (GluR1). Our results indicate that Sez6l2 is one of the auxiliary subunits of the AMPA receptor and acts as a scaffolding protein to link GluR1 to ADD. Furthermore, Sez6l2 overexpression upregulates ADD phosphorylation, whereas siRNA-mediated downregulation of Sez612 prevents ADD phosphorylation, suggesting that Sez6l2 modulates AMPA-ADD signal transduction..
16. Keiichi Nakayama, Robotic crowd biology with Maholo LabDroids, 2017.07.
17. Keiichi Nakayama, Hippo signaling suppresses cell ploidy and tumorigenesis through Skp2, CANCER CELL, 10.1016/j.ccell.2017.04.004, 31, 5, 669-+, 2017.05.
18. Keiichi Nakayama, FBXL5 inactivation in mouse brain induces aberrant proliferation of neural stem progenitor cells, MOLECULAR AND CELLULAR BIOLOGY, 10.1128/MCB.00470-16, 37, 8, 2017.04.
19. Keiichi Nakayama, A large-scale targeted proteomics assay resource based on an in vitro human proteome, NATURE METHODS, 10.1038/NMETH.4116, 14, 3, 251-+, 2017.03.
20. Keiichi Nakayama, GRWD1 negatively regulates p53 via the RPL11-MDM2 pathway and promotes tumorigenesis, EMBO REPORTS, 10.15252/embr.201642444, 18, 1, 123-137, 2017.01.
21. Keiichi Nakayama, mTORC1 and muscle regeneration are regulated by the LINC00961-encoded SPAR polypeptide, NATURE, 10.1038/nature21034, 541, 7636, 228-+, 2017.01.
22. Keiichi Nakayama, SRRM4-dependent neuron-specific alternative splicing of protrudin transcripts regulates neurite outgrowth, SCIENTIFIC REPORTS, 10.1038/srep41130, 7, 2017.01.
23. Keiichi Nakayama, The SCF beta-TRCP E3 ubiquitin ligase complex targets Lipin1 for ubiquitination and degradation to promote hepatic lipogenesis, SCIENCE SIGNALING, 10.1126/scisignal.aah4117, 10, 460, 2017.01.
24. Keiichi Nakayama, The novel heart-specific RING finger protein 207 is involved in energy metabolism in cardiomyocytes, JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 10.1016/j.yjmcc.2016.09.013, 100, 43-53, 2016.11.
25. Keiichi Nakayama, Phosphoproteomics analyses show subnetwork systems in T-cell receptor signaling, GENES TO CELLS, 10.1111/gtc.12406, 21, 10, 1095-1112, 2016.10.
26. Keiichi Nakayama, FBXW7 is involved in the acquisition of the malignant phenotype in epithelial ovarian tumors, CANCER SCIENCE, 10.1111/cas.13026, 107, 10, 1399-1405, 2016.10.
27. Keiichi Nakayama, Role of apolipoprotein B100 and oxidized low-density lipoprotein in the monocyte tissue factor induction mediated by anti-2 glycoprotein I antibodies, LUPUS, 10.1177/0961203316638165, 25, 12, 1288-1298, 2016.10.
28. Keiichi Nakayama, CHD8 haploinsufficiency results in autistic-like phenotypes in mice, NATURE, 10.1038/nature19357, 537, 7622, 675-+, 2016.09.
29. Keiichi Nakayama, p57(Kip2) knock-in mouse reveals CDK-independent contribution in the development of Beckwith-Wiedemann syndrome, JOURNAL OF PATHOLOGY, 10.1002/path.4721, 239, 3, 250-261, 2016.07.
30. Keiichi Nakayama, FBXL12 regulates T-cell differentiation in a cell-autonomous manner, STEM CELLS, 10.1111/gtc.12360, 21, 5, 517-524, 2016.05.
31. Keiichi Nakayama, Akt1-mediated Gata3 phosphorylation controls the repression of IFN gamma in memory-type Th2 cells, NATURE COMMUNICATIONS, 10.1038/ncomms11289, 7, 2016.04.
32. Keiichi Nakayama, UV damage-induced phosphorylation of HBO1 triggers CRL4(DDB2)-mediated degradation to regulate cell proliferation, MOLECULAR AND CELLULAR BIOLOGY, 10.1128/MCB.00809-15, 36, 3, 394-406, 2016.02.
33. Keiichi Nakayama, FBXL12-mediated degradation of ALDH3 is essential for trophoblast differentiation during placental development, STEM CELLS, 10.1002/stem.2088, 33, 11, 3327-3340, 2015.11.
34. Keiichi Nakayama, Maternal TET3 is dispensable for embryonic development but is required for neonatal growth, SCIENTIFIC REPORTS, 10.1038/srep15876, 5, 15876, 2015.09.
35. Keiichi Nakayama, Role of the Atg9a gene in intrauterine growth and survival of fetal mice, REPRODUCTIVE BIOLOGY, 10.1016/j.repbio.2015.05.001, 15, 3, 131-138, 2015.09.
36. Keiichi Nakayama, Tissue-specific expression of histone H3 variants diversified after species separation, EPIGENETICS & CHROMATIN, 10.1186/s13072-015-0027-3, 8, 2015.09.
37. Keiichi Nakayama, K63-linked JARID1B ubiquitination by TRAF6 contributes to aberrant elevation of JARID1B in prostate cancer, CANCER RESEARCH, 10.1158/1538-7445.AM2015-90, 75, 2015.08.
38. Keiichi Nakayama, F-box protein FBXW7 inhibits-cancer metastasis in a non-cell-autonomous manner, JOURNAL OF CLINICAL INVESTIGATION, 10.1172/JCI78782, 125, 2, 621-635, 2015.02, 有名ながん抑制遺伝子産物であるFbxw7が、がん細胞内部だけでなく、がんニッチにおいてもがん転移を抑制することを明らかにした。Fbxw7はNotchを分解することによって、ケモカインCCL2の発現を負に制御しているが、骨髄細胞特異的Fbxw7欠損マウスでは間葉系幹細胞におけるCCL2が上昇しており、がんニッチにおいて単球/マクロファージの浸潤を促す結果、がん転移が促進する。この現象は、マウスだけではなくヒト乳がん患者における末梢血中のFbxw7 mRNA量と予後における相関があることからも、種間を超えて保存されていることが推測される。またマウスにおいてCCL2を抑制する既存薬プロパゲルマニウムを投与すると、がん転移が強力に阻害された。このことはヒトにおけるがん治療にプロパゲルマニウムががん転移抑制剤として利用できることを示唆するものである。.
39. Keiichi Nakayama, MDM2 Mediates Nonproteolytic Polyubiquitylation of the DEAD-Box RNA Helicase DDX24, MOLECULAR AND CELLULAR BIOLOGY, 10.1128/MCB.00320-14, 34, 17, 3321-3340, 2014.09.
40. Keiichi Nakayama, Role of the ANKMY2-FKBP38 Axis in Regulation of the Sonic Hedgehog (Shh) Signaling Pathway, JOURNAL OF BIOLOGICAL CHEMISTRY, 10.1074/jbc.M114.558635, 289, 37, 25639-25654, 2014.09.
41. Keiichi Nakayama, HERC2 Targets the Iron Regulator FBXL5 for Degradation and Modulates Iron Metabolism, JOURNAL OF BIOLOGICAL CHEMISTRY, 10.1074/jbc.M113.541490, 289, 23, 16430-16441, 2014.06.
42. Yutaka Hashimoto, Michiko Shirane, Fumiko Matsuzaki, Takafumi Ohnishi, Keiichi Nakayama, Protrudin Regulates Endoplasmic Reticulum Morphology and Function Associated with the Pathogenesis of Hereditary Spastic Paraplegia, JOURNAL OF BIOLOGICAL CHEMISTRY, 10.1074/jbc.M113.528687, 289, 19, 12946-12961, 2014.05.
43. Keiichi Nakayama, Tyk2-Dependent Bystander Activation of Conventional and Nonconventional Th1 Cell Subsets Contributes to Innate Host Defense against Listeria monocytogenes Infection, JOURNAL OF IMMUNOLOGY, 10.4049/jimmunol.1303067, 192, 10, 4739-4747, 2014.05.
44. Matsumoto Akinobu, Shoichiro Takeishi, Keiichi Nakayama, p57 regulates T-cell development and prevents lymphomagenesis by balancing p53 activity and pre-TCR signaling, BLOOD, 10.1182/blood-2013-10-532390, 123, 22, 3429-3439, 2014.05, T cells are key components of the immune system, playing a central role in cell-mediated immunity. The sequential differentiation of T cells is associated with strict regulation of the cell cycle at each developmental stage. A balance between p53 activity and pre-T cell receptor (TCR) signaling regulates proliferation and differentiation decisions made by these cells. The relation between maintenance of this balance and the function of cell cycle regulators has remained largely unknown, however. We now show that mice with T cell-specific deficiency of the cyclin-dependent kinase inhibitor p57 manifest a differentiation block at the early stage of T cell maturation. Further genetic analysis showed that this defect is attributable to an imbalance between p53 activity and pre-TCR signaling caused by hyperactivation of the E2F-p53 pathway. Moreover, ablation of both p57 and p53 in T cells led to the development of aggressive thymic lymphomas with a reduced latency compared with that apparent for p53-deficient mice, whereas ablation of p57 alone did not confer susceptibility to this hematologic malignancy. Our results thus show that the p57-E2F-p53 axis plays a pivotal role in the proper development of T cells as well as in the prevention of lymphomagenesis..
45. Keiichi Nakayama, Skp2 suppresses apoptosis in Rb1-deficient tumours by limiting E2F1 activity, NATURE COMMUNICATIONS, 10.1038/ncomms4463, 5, 2014.03.
46. Takafumi Ohnishi, Michiko Shirane, Yutaka Hashimoto, Keiichi Nakayama, Identification and characterization of a neuron-specific isoform of protrudin, GENES TO CELLS, 10.1111/gtc.12109, 19, 2, 97-111, 2014.02.
47. Keiichi Nakayama, p27 is regulated independently of Skp2 in the absence of Cdk2, BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, 10.1016/j.bbamcr.2013.11.005, 1843, 2, 436-445, 2014.02.
48. Keiichi Nakayama, Identification of anti-Sez612 antibody in a patient with cerebellar ataxia and retinopathy, JOURNAL OF NEUROLOGY, 10.1007/s00415-013-7134-5, 261, 1, 224-226, 2014.01.
49. Keiichi Nakayama, CDK inhibitors, p21(Cip1) and p27(Kip1), participate in cell cycle exit of mammalian cardiomyocytes, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 10.1016/j.bbrc.2013.12.109, 443, 3, 1105-1109, 2014.01.
50. Keiichi Nakayama, Skp2 Deletion Unmasks a p27 Safeguard that Blocks Tumorigenesis in the Absence of pRb and p53 Tumor Suppressors, CANCER CELL, 10.1016/j.ccr.2013.09.021, 24, 5, 645-659, 2013.11.
51. Kanae Yumimoto, Tetsuya Muneoka, Tomohiro Tsuboi, Keiichi Nakayama, Substrate Binding Promotes Formation of the Skp1-Cul1-Fbxl3 (SCFFbxl3) Protein Complex, JOURNAL OF BIOLOGICAL CHEMISTRY, 10.1074/jbc.M113.511303, 288, 45, 32766-32776, 2013.11.
52. Kanae Yumimoto, Masaki Matsumoto, Keiichi Nakayama, F-box and WD Repeat Domain-containing-7 (Fbxw7) Protein Targets Endoplasmic Reticulum-anchored Osteogenic and Chondrogenic Transcriptional Factors for Degradation, JOURNAL OF BIOLOGICAL CHEMISTRY, 10.1074/jbc.M113.465179, 288, 40, 28488-28502, 2013.10.
53. Keiichi Nakayama, Phosphorylation of Noxo1 at threonine 341 regulates its interaction with Noxa1 and the superoxide-producing activity of Nox1, FEBS JOURNAL, 10.1111/febs.12489, 280, 20, 5145-5159, 2013.10.
55. Keiichi Nakayama, Loss of Protein Kinase C-delta Protects against LPS-Induced Osteolysis Owing to an Intrinsic Defect in Osteoclastic Bone Resorption, JOURNAL OF BIOLOGICAL CHEMISTRY, 10.1371/journal.pone.0070815, 8, 8, 2013.08.
56. Keiichi Nakayama, Opposing functions of Fbxw7 in keratinocyte growth, differentiation and skin tumorigenesis mediated through negative regulation of c-Myc and Notch, ONCOGENE, 10.1038/onc.2012.213, 32, 15, 1921-1932, 2013.04.
57. Keiichi Nakayama, p57 controls adult neural stem cell quiescence and modulates the pace of lifelong neurogenesis, EMBO JOURNAL, 10.1038/emboj.2013.50, 32, 7, 970-981, 2013.04.
58. Linsey Reavie, Shannon M. Buckley, Evangelia Loizou, Shoichiro Takeishi, Beatriz Aranda-Orgilles, Delphine Ndiaye-Lobry, Omar Abdel-Wahab, Sherif Ibrahim, Keiichi Nakayama, Iannis Aifantis, Regulation of c-Myc Ubiquitination Controls Chronic Myelogenous Leukemia Initiation and Progression, CANCER CELL, 10.1016/j.ccr.2013.01.025, 23, 3, 362-375, 2013.03.
59. Shoichiro Takeishi, Matsumoto Akinobu, Ichiro Onoyama, Ichiro Naka, Atsushi Hirao, Keiichi Nakayama, Ablation of Fbxw7 Eliminates Leukemia-Initiating Cells by Preventing Quiescence, CANCER CELL, 10.1016/j.ccr.2013.01.026, 23, 3, 347-361, 2013.03, Imatinib eradicates dividing progenitor cells of chronic myeloid leukemia (CML) but does not effectively target nondividing leukemia-initiating cells (LICs); thus, the disease often relapse after its discontinuation. We now show that Fbxw7 plays a pivotal role in maintenance of quiescence in LICs of CML by reducing the level of c-Myc. Abrogation of quiescence in LICs by Fbxw7 ablation increased their sensitivity to imatinib, and the combination of Fbxw7 ablation with imatinib treatment resulted in a greater depletion of LICs than of normal hematopoietic stem cells in mice. Purging of LICs by targeting Fbxw7 to interrupt their quiescence and subsequent treatment with imatinib may thus provide the basis for a promising therapeutic approach to CML..
60. Arisa Hirano, Kanae Yumimoto, Ryosuke Tsunematsu, Masaki Matsumoto, Masaaki Oyama, Hiroko Kozuka-Hata, Tomoki Nakagawa, Darin Lanjakornsiripan, Keiichi Nakayama, Yoshitaka Fukada, FBXL21 Regulates Oscillation of the Circadian Clock through Ubiquitination and Stabilization of Cryptochromes, CELL, 10.1016/j.cell.2013.01.054, 152, 5, 1106-1118, 2013.02, In the mammalian circadian clockwork, CRY1 and CRY2 repressor proteins are regulated by posttranslational modifications for temporally coordinated transcription of clock genes. Previous studies revealed that FBXL3, an F-box-type E3 ligase, ubiquitinates CRYs and mediates their degradation. Here, we found that FBXL21 also ubiquitinates CRYs but counteracts FBXL3. Fbxl21(-/-) mice exhibited normal periodicity of wheel-running rhythms with compromised organization of daily activities, while an extremely long-period phenotype of Fbxl3(-/-) mice was attenuated in Fbxl3/Fbxl21 double-knockout mice. The double knockout destabilized the behavioral rhythms progressively and sometimes elicited arrhythmicity. Surprisingly, FBXL21 stabilized CRYs and antagonized the destabilizing action by FBXL3. Predominantly cytosolic distribution of FBXL21 contrasts with nuclear localization of FBXL3. These results emphasize the physiological importance of antagonizing actions between FBXL21 and FBXL3 on CRYs, and their combined actions at different subcellular locations stabilize oscillation of the circadian clock..
61. Shotaro Saita, Michiko Shirane, Keiichi Nakayama, Selective escape of proteins from the mitochondria during mitophagy, NATURE COMMUNICATIONS, 10.1038/ncomms2400, 4, 2013.01.
62. Yasutaka Okita, Keiichi Nakayama, UPS Delivers Pluripotency, CELL STEM CELL, 10.1016/j.stem.2012.11.009, 11, 6, 728-730, 2012.12.
63. Hidefumi Fukushima, Matsumoto Akinobu, Hiroyuki Inuzuka, Bo Zhai, Alan W. Lau, Lixin Wan, Daming Gao, Shavali Shaik, Min Yuan, Steven P. Gygi, Eijiro Jimi, John M. Asara, Keiko Nakayama, Wenyi Wei, Keiichi Nakayama, SCFFbw7 Modulates the NF kappa B Signaling Pathway by Targeting NF kappa B2 for Ubiquitination and Destruction, CELL REPORTS, 10.1016/j.celrep.2012.04.002, 1, 5, 434-443, 2012.05.
64. Chia-Hsin Chan, Chien-Feng Li, Wei-Lei Yang, Yuan Gao, Szu-Wei Lee, Zizhen Feng, Hsuan-Ying Huang, Leo G. Flores, Kelvin K.C. Tsai, Yiping Shao, John D. Hazle, Dihua Yu, Wenyi Wei, Dos Sarbassov, Mien-Chie Hung, Keiichi Nakayama, Hui-Kuan Lin, The Skp2-SCF E3 Ligase Regulates Akt Ubiquitination, Glycolysis, Herceptin Sensitivity, and Tumorigenesis, CELL, 10.1016/j.cell.2012.02.065, 149, 5, 1098-1111, 2012.05.
65. Moroishi, T., Nishiyama, M., Takeda, Y., Iwai, K., Nakayama, K.I., The FBXL5-IRP2 axis is integral to control of iron metabolism in vivo, Cell Metabolism, 14: 339-51, 2011.09, Iron-dependent degradation of iron-regulatory protein 2 (IRP2) is a key event for maintenance of an appropriate intracellular concentration of iron. Although FBXL5 (F-box and leucine-rich repeat protein 5) is thought to mediate this degradation, the role of FBXL5 in the control of iron homeostasis in vivo has been poorly understood. We have now found that mice deficient in FBXL5 died in utero associated with excessive iron accumulation. This embryonic mortality was prevented by additional ablation of IRP2, suggesting that impaired IRP2 degradation is primarily responsible for the death of Fbxl5–/– mice. We also found that liver-specific deletion of Fbxl5 resulted in deregulation of both hepatic and systemic iron homeostasis, leading to the development of steatohepatitis. The liver-specific mutant mice died with acute liver failure when fed a high iron diet. Our results thus uncover a major role for FBXL5 in ensuring an appropriate supply of iron to cells..
66. Matsumoto, A., Takeishi, S., Kanie, T., Susaki, E., Onoyama, I., Tateishi, Y., Nakayama, K., Nakayama, K.I., p57 is required for quiescence and maintenance of adult hematopoietic stem cells, Cell Stem Cell, 9: 262-71, 2011.09, Quiescence is required for maintenance of hematopoietic stem cells (HSCs). Members of the Cip/Kip family of cyclin-dependent kinase (CDK) inhibitors (p21, p27, p57) have been implicated in quiescence of HSCs, but loss of p21 or p27 in mice affects neither quiescence nor stemness of HSCs except under certain conditions. Although p57 is most abundant in the quiescent HSCs, its function in HSCs has remained uncharacterized. Here we show that the self-renewal capacity of p57-deficient HSCs was severely impaired, and the proportion of the cells in G0 phase was also reduced. Additional ablation of p21 on the p57-null background resulted in a further decrease in colony-forming activity of HSCs. Moreover, the HSC abnormalities of p57-deficient mice were corrected by knock-in of the gene for p27 at the p57 locus. Our results thus suggest that, among Cip/Kip CDK inhibitors, p57 plays the predominant role in the quiescence and maintenance of adult HSCs..
67. Onoyama, I., Suzuki, A., Matsumoto, A., Tomita, K., Katagiri, H., Oike, Y., Nakayama, K., Nakayama, K.I., Fbxw7 regulates lipid metabolism and cell fate decisions in the mouse liver, J. Clin. Invest., 121, 342-354, 2011.01, E3 ubiquitin ligase complexes of the SCF type consist of ring-box 1 (Rbx1), cullin 1 (Cul1), S-phase kinase-associated protein 1 (Skp1), and a member of the F-box family of proteins. The identity of the F-box protein determines the substrate specificity of the complex. The F-box family member F-box- and WD repeat domain-containing 7 (Fbxw7; also known as Fbw7, SEL-10, hCdc4, and hAgo) targets for degradation proteins with wide-ranging functions, and uncovering its in vivo role has been difficult, because Fbxw7-/- embryos die in utero. Using two different Cre-loxP systems (Mx1-Cre and Alb-Cre), we generated mice with liver-specific null mutations of Fbxw7. Hepatic ablation of Fbxw7 resulted in hepatomegaly and steatohepatitis, with massive deposition of triglyceride, a phenotype similar to that observed in humans with nonalcoholic steatohepatitis. Both cell proliferation and the abundance of Fbxw7 substrates were increased in the Fbxw7-deficient liver. Long-term Fbxw7 deficiency resulted in marked proliferation of the biliary system and the development of hamartomas. Fbxw7 deficiency also skewed the differentiation of liver stem cells toward the cholangiocyte lineage rather than the hepatocyte lineage in vitro. This bias was corrected by additional loss of the Notch cofactor RBP-J, suggesting that Notch accumulation triggered the abnormal proliferation of the biliary system. Together, our results suggest that Fbxw7 plays key roles, regulating lipogenesis and cell proliferation and differentiation in the liver..
68. Liu Z, Liu X, Nakayama KI, Nakayama K, Ye K., Protein kinase C-delta phosphorylates Ebp1 and prevents its proteolytic degradation, enhancing cell survival., J Neurochem., 100(5):1278-88., 2007.03.
69. Moller C, Karlberg M, Abrink M, Nakayama KI, Motoyama N, Nilsson G., Bcl-2 and Bcl-XL are indispensable for the late phase of mast cell development from mouse embryonic stem cells., Exp Hematol., 35(3):385-93., 2007.03.
70. Tu X, Joeng KS, Nakayama KI, Nakayama K, Rajagopal J, Carroll TJ, McMahon A., Noncanonical Wnt signaling through G protein-linked PKCdelta activation promotes bone formation., Dev Cell. , 12(1):113-27., 2007.01.
71. Uchida T, Iwashita N, Ohara-Imaizumi M, Ogihara T, Nagai S, Choi JB, Tamura Y, Tada N, Kawamori R, Nakayama KI, Nagamatsu S, Watada H., Protein kinase Cdelta plays a non-redundant role in insulin secretion in pancreatic beta cells., J Biol Chem., 282(4):2707-16., 2007.01.
72. Shukla A, Lounsbury KM, Barrett TF, Gell J, Rincon M, Butnor KJ, Taatjes DJ, Davis GS, Vacek P, Nakayama KI, Nakayama K, Steele C, Mossman BT., Asbestos-induced peribronchiolar cell proliferation and cytokine production are attenuated in lungs of protein kinase C-knockout mice., J Biol Chem., 170(1):140-51., 2007.01.
73. Sakai T, Sakaue H, Nakamura T, Okada M, Matsuki Y, Watanabe E, Hiramatsu R, Nakayama K, Nakayama KI, Kasuga M., Skp2 controls adipocyte proliferation during the development of obesity., J Biol Chem., 282(3):2038-46., 2007.01.
74. Yanagawa M, Tsukuba T, Nishioku T, Okamoto Y, Okamoto K, Takii R, Terada Y, Nakayama KI, Kadowaki T, Yamamoto K., Cathepsin E deficiency induces a novel form of lysosomal storage disorder showing the accumulation of lysosomal membrane sialoglycoproteins and the elevation of lysosomal pH in macrophages., J Biol Chem., 82(3):1851-62., 2007.01.
75. Itoh Y, Masuyama N, Nakayama K, Nakayama KI, Gotoh Y., The cyclin-dependent kinase inhibitors p57 and p27 regulate neuronal migration in the developing mouse neocortex., J Biol Chem., 282(1):390-6., 2007.01.
76. Shirane M, Nakayama KI., Protrudin induces neurite formation by directional membrane trafficking., Science., 314(5800):818-21., 2006.11.
77. Matsumoto A, Onoyama I, Nakayama KI., Expression of mouse Fbxw7 isoforms is regulated in a cell cycle- or p53-dependent manner., Biochem Biophys Res Commun., 3350(1):114-9., 2006.11.
78. Hara K, Nakayama KI, Nakayama K., Geminin is essential for the development of preimplantation mouse embryos., Genes Cells., 11(11):1281-93., 2006.11.
79. Tsunematsu R, Nishiyama M, Kotoshiba S, Saiga T, Kamura T, Nakayama KI., Fbxw8 is essential for Cul1-Cul7 complex formation and for placental development., Mol Cell Biol., 26(16):6157-69., 2006.10.
80. Fujii Y, Yada M, Nishiyama M, Kamura T, Takahashi H, Tsunematsu R, Susaki E, Nakagawa T, Matsumoto A, Nakayama KI., Fbxw7 contributes to tumor suppression by targeting multiple proteins for ubiquitin-dependent degradation., Cancer Sci., 97(8):729-36., 2006.10.
81. Parcellier A, Brunet M, Schmitt E, Col E, Didelot C, Hammann A, Nakayama K, Nakayama KI, Khochbin S, Solary E, Garrido C., HSP27 favors ubiquitination and proteasomal degradation of p27Kip1 and helps S-phase re-entry in stressed cells., FASEB J., 20(8):1179-81., 2006.06.
82. Yoshida K, Yamaguchi T, Shinagawa H, Taira N, Nakayama KI, Miki Y., Protein kinase C delta activates topoisomerase IIalpha to induce apoptotic cell death in response to DNA damage., Mol Cell Biol., 26(9):3414-31., 2006.06.
83. Fotovati A, Nakayama K, Nakayama KI., Impaired germ cell development due to compromised cell cycle progression in Skp2-deficient mice., Cell Div., 1:4., 2006.04.
84. Humphries MJ, Limesand KH, Schneider JC, Nakayama KI, Anderson SM, Reyland ME., Suppression of apoptosis in the protein kinase Cdelta null mouse in vivo., J Biol Chem., 281(14):9728-37., 2006.04.
85. Kase S, Yoshida K, Ohgami K, Shiratori K, Ohno S, Nakayama KI., phorylation of p27(KIP1) in the mitotic cells of the corneal epithelium., Curr Eye Res., 31(4):307-12., 2006.04.
86. Nishitani H, Sugimoto N, Roukos V, Nakanishi Y, Saijo M, Obuse C, Tsurimoto T, Nakayama KI, Nakayama K, Fujita M, Lygerou Z, Nishimoto T., Two E3 ubiquitin ligases, SCF-Skp2 and DDB1-Cul4, target human Cdt1 for proteolysis., EMBO J., 25(5):1126-36., 2006.03.
87. Kase S, Yoshida K, Ohgami K, Shiratori K, Suzuki Y, Nakayama KI, Ohno S., Expression of cdc2 and p27(KIP1) phosphorylation in mitotic cells of the human retinoblastoma., Int J Mol Med., 17(3):465-8., 2006.03.
88. Kase S, Yoshida K, Harada T, Harada C, Namekata K, Suzuki Y, Ohgami K, Shiratori K, Nakayama KI, Ohno S., Phosphorylation of extracellular signal-regulated kinase and p27(KIP1) after retinal detachment., Graefes Arch Clin Exp Ophthalmol., 244(3):352-8, 2006.03.
89. Shirane M, Nakayama KI., Inherent calcineurin inhibitor FKBP38 targets Bcl-2 to mitochondria and inhibits apoptosis., Nature Cell Biol., 10.1038/ncb894, 5, 1, 28-37, 5(1): 28-37, 2003.01.