研究者詳細 - 木下　専

論文 - 木下　専

分割表示 103 件中 21 - 40 件目／全件表示 >>

Silent information regulator 2 homolog 1 (SIRT1) counters cerebral hypoperfusion injury by deacetylating endothelial nitric oxide synthase (eNOS). 査読有り国際共著

Hattori Y, Okamoto Y, Maki T, Yamamoto Y, Oishi N, Yamahara K, Takahashi R, Kalaria RN, Fukuyama H, Kinoshita M, Ihara M.

Stroke 45 巻 ( 11 ) 頁： 3403 - 3411 2014年11月

Genetic deletion of SEPT7 reveals a cell type-specific role of septins in microtubule destabilization for the completion of cytokinesis. 査読有り国際共著国際誌

Manoj B Menon, Akihiro Sawada, Anuhar Chaturvedi, Pooja Mishra, Karin Schuster-Gossler, Melanie Galla, Axel Schambach, Achim Gossler, Reinhold Förster, Michael Heuser, Alexey Kotlyarov, Makoto Kinoshita, Matthias Gaestel

PLoS Genetics 10 巻 ( 8 ) 頁： e1004558 2014年8月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Public Library of Science ({PLoS})

Cytokinesis terminates mitosis, resulting in separation of the two sister cells. Septins, a conserved family of GTP-binding cytoskeletal proteins, are an absolute requirement for cytokinesis in budding yeast. We demonstrate that septin-dependence of mammalian cytokinesis differs greatly between cell types: genetic loss of the pivotal septin subunit SEPT7 in vivo reveals that septins are indispensable for cytokinesis in fibroblasts, but expendable in cells of the hematopoietic system. SEPT7-deficient mouse embryos fail to gastrulate, and septin-deficient fibroblasts exhibit pleiotropic defects in the major cytokinetic machinery, including hyperacetylation/stabilization of microtubules and stalled midbody abscission, leading to constitutive multinucleation. We identified the microtubule depolymerizing protein stathmin as a key molecule aiding in septin-independent cytokinesis, demonstrated that stathmin supplementation is sufficient to override cytokinesis failure in SEPT7-null fibroblasts, and that knockdown of stathmin makes proliferation of a hematopoietic cell line sensitive to the septin inhibitor forchlorfenuron. Identification of septin-independent cytokinesis in the hematopoietic system could serve as a key to identify solid tumor-specific molecular targets for inhibition of cell proliferation.

DOI： 10.1371/journal.pgen.1004558

Web of Science

PubMed

Phosphatidic Acid (PA)-preferring Phospholipase A1 Regulates Mitochondrial Dynamics. 査読有り国際共著

Baba T, Kashiwagi Y, Arimitsu N, Kogure T, Edo A, Maruyama T, Nakao K, Nakanishi H, Kinoshita M, Frohman MA, Yamamoto A, Tani K

The Journal of Biological Chemistry 289 巻 ( 16 ) 頁： 11497 - 11511 2014年4月

SIRT1 overexpression ameliorates a mouse model of SOD1-linked amyotrophic lateral sclerosis via HSF1/HSP70i chaperone system 査読有り

Seiji Watanabe, Natsumi Ageta-Ishihara, Shinji Nagatsu, Keizo Takao, Okiru Komine, Fumito Endo, Tsuyoshi Miyakawa, Hidemi Misawa, Ryosuke Takahashi, Makoto Kinoshita, Koji Yamanaka

Molecular Brain 7 巻 ( 1 ) 頁： 62 - 62 2014年

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Springer Science $\mathplus$ Business Media

Background: Dominant mutations in superoxide dismutase 1 (SOD1) cause degeneration of motor neurons in a subset of inherited amyotrophic lateral sclerosis (ALS). The pathogenetic process mediated by misfolded and/or aggregated mutant SOD1 polypeptides is hypothesized to be suppressed by protein refolding. This genetic study is aimed to test whether mutant SOD1-mediated ALS pathology recapitulated in mice could be alleviated by overexpressing a longevity-related deacetylase SIRT1 whose substrates include a transcription factor heat shock factor 1 (HSF1), the master regulator of the chaperone system.
Results: We established a line of transgenic mice that chronically overexpress SIRT1 in the brain and spinal cord. While inducible HSP70 (HSP70i) was upregulated in the spinal cord of SIRT1 transgenic mice (PrP-Sirt1), no neurological and behavioral alterations were detected. To test hypothetical benefits of SIRT1 overexpression, we crossbred PrP-Sirt1 mice with two lines of ALS model mice: A high expression line that exhibits a severe phenotype (SOD1(G93A)-H) or a low expression line with a milder phenotype (SOD1(G93A)-L). The Sirt1 transgene conferred longer lifespan without altering the time of symptomatic onset in SOD1(G93A)-L. Biochemical analysis of the spinal cord revealed that SIRT1 induced HSP70i expression through deacetylation of HSF1 and that SOD1(G93A)-L/PrP-Sirt1 double transgenic mice contained less insoluble SOD1 than SOD1(G93A)-L mice. Parallel experiments showed that Sirt1 transgene could not rescue a more severe phenotype of SOD1(G93A)-H transgenic mice partly because their HSP70i level had peaked out.
Conclusions: The genetic supplementation of SIRT1 can ameliorate a mutant SOD1-linked ALS mouse model partly through the activation of the HSF1/HSP70i chaperone system. Future studies shall include testing potential benefits of pharmacological enhancement of the deacetylation activity of SIRT1 after the onset of the symptom.

DOI： 10.1186/s13041-014-0062-1

Web of Science

Septins promote dendrite and axon development by negatively regulating microtubule stability via HDAC6-mediated deacetylation. 査読有り国際共著

Ageta-Ishihara N, Miyata T, Ohshima C, Watanabe M, Sato Y, Hamamura Y, Higashiyama T, Mazitschek R, Bito H, Kinoshita M.

Nature Communications 4 巻 ( 2532 ) 2013年10月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

Neurite growth requires two guanine nucleotide-binding protein polymers of tubulins and septins. However, whether and how those cytoskeletal systems are coordinated was unknown. Here we show that the acute knockdown or knockout of the pivotal septin subunit SEPT7 from cerebrocortical neurons impairs their interhemispheric and cerebrospinal axon projections and dendritogenesis in perinatal mice, when the microtubules are severely hyperacetylated. The resulting hyperstabilization and growth retardation of microtubules are demonstrated in vitro. The phenotypic similarity between SEPT7 depletion and the pharmacological inhibition of α-tubulin deacetylase HDAC6 reveals that HDAC6 requires SEPT7 not for its enzymatic activity, but to associate with acetylated α-tubulin. These and other findings indicate that septins provide a physical scaffold for HDAC6 to achieve efficient microtubule deacetylation, thereby negatively regulating microtubule stability to an optimal level for neuritogenesis. Our findings shed light on the mechanisms underlying the HDAC6-mediated coupling of the two ubiquitous cytoskeletal systems during neural development.

DOI： 10.1038/ncomms3532

Chronic overload of SEPT4, a parkin substrate that aggregates in Parkinson's disease, causes behavioral alterations but not neurodegeneration in mice. 査読有り国際誌

Natsumi Ageta-Ishihara, Hodaka Yamakado, Takao Morita, Satoko Hattori, Keizo Takao, Tsuyoshi Miyakawa, Ryosuke Takahashi, Makoto Kinoshita

Molecular Brain 6 巻 ( 1 ) 頁： 35 - 35 2013年8月

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：BIOMED CENTRAL LTD

BACKGROUND: In autosomal recessive early-onset Parkinsonism (PARK2), the pathogenetic process from the loss of function of a ubiquitin ligase parkin to the death of dopamine neurons remains unclear. A dominant hypothesis attributes the neurotoxicity to accumulated substrates that are exempt from parkin-mediated degradation. Parkin substrates include two septins; SEPT4/CDCrel-2 which coaggregates with α-synuclein as Lewy bodies in Parkinson's disease, and its closest homolog SEPT5/CDCrel-1/PNUTL1 whose overload with viral vector can rapidly eliminate dopamine neurons in rats. However, chronic effects of pan-neural overload of septins have never been examined in mammals. To address this, we established a line of transgenic mice that express the largest gene product SEPT4(54kDa) via the prion promoter in the entire brain. RESULTS: Histological examination and biochemical quantification of SEPT4-associated proteins including α-synuclein and the dopamine transporter in the nigrostriatal dopamine neurons found no significant difference between Sept4(Tg/+) and wild-type littermates. Thus, the hypothetical pathogenicity by the chronic overload of SEPT4 alone, if any, is insufficient to trigger neurodegenerative process in the mouse brain. Intriguingly, however, a systematic battery of behavioral tests revealed unexpected abnormalities in Sept4(Tg/+) mice that include consistent attenuation of voluntary activities in distinct behavioral paradigms and altered social behaviors. CONCLUSIONS: Together, these data indicate that septin dysregulations commonly found in postmortem human brains with Parkinson's disease, schizophrenia and bipolar disorders may be responsible for a subset of behavioral abnormalities in the patients.

DOI： 10.1186/1756-6606-6-35

Web of Science

Scopus

PubMed

セプチンによるドーパミン神経伝達機構の制御招待有り

木下　専、田（石原）奈津実

脳21 特集トランスポートソーム：トランスポーター・チャネル群の相互作用に基づく神経系の機能構築 16 巻 ( 3 ) 頁： 40 - 45 2013年7月

運動による脳の活性化のしくみ招待有り査読有り

Ageta-Ishihara N, Morita T, Yamauchi Y, Kinoshita M

健康医科学 28 巻頁： 44 - 51 2013年3月

Localization of septin proteins in the mouse cochlea. 査読有り国際共著国際誌

Atsuhiro Yoshida, Norio Yamamoto, Makoto Kinoshita, Noboru Hiroi, Takeshi Hiramoto, Gina Kang, William S Trimble, Kenji Tanigaki, Takayuki Nakagawa, Juichi Ito

Hearing Research 289 巻 ( 1-2 ) 頁： 40 - 51 2012年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Elsevier {BV}

Septins are a family of GTP binding proteins that are well conserved in eukaryotic species except plants. Septins contribute to the lateral compartmentalization of membranes, cortical rigidity, and the regulation of membrane trafficking by associating with membrane lipids, actin, and microtubules. The organ of Corti in the cochlea has pivotal roles in auditory perception and includes two kinds of highly polarized cells, hair and supporting cells, both of which are rich in actin and microtubules. To identify the roles of septins in the cochlea, we analyzed the localization of three septin proteins, septin 4 (SEPT4), septin 5 (SEPT5), and septin 7 (SEPT7) that are abundantly expressed in brain tissues, and also examined auditory functions of Sept4 and Sept5 null mice. SEPT4, SEPT5, and SEPT7 were expressed in inner and outer pillar cells and Deiters' cells but the distribution patterns of each protein in Deiters' cells were different. SEPT4 and SEPT7 were expressed in the phalangeal process where SEPT5 was not detected. In addition to these cells SEPT5 and SEPT7 were co-localized with presynaptic vesicles of efferent nerve terminals. Only SEPT7 was expressed in the cochlea at embryonic stages. Although expression patterns of septin proteins suggested their important roles in the function of the cochlea, both Sept4 and Sept5 null mice had similar auditory functions to their wild type littermates. Immunohistochemical analysis of Sept4 null mice showed that compensatory expression of SEPT5 in the phalangeal process of Deiters' cells may have caused functional compensation of hearing ability in Sept4 null mice.

DOI： 10.1016/j.heares.2012.04.015

Web of Science

PubMed

ドーパミン神経伝達と変性におけるセプチン細胞骨格系の役割招待有り

日本神経精神薬理学会誌 32 巻 ( 1 ) 頁： 25 - 9 2012年2月

セプチン招待有り査読有り

上田（石原）奈津実、木下　専

脳科学辞典 2012年

セプチン招待有り

上谷　大介、木下　専

日本細胞生物学会　細胞生物学用語集 2012年

Downregulation of the Wnt antagonist Dkk2 links the loss of Sept4 and myofibroblastic transformation of hepatic stellate cells. 査読有り国際誌

Atsuko Yanagida, Keiko Iwaisako, Etsuro Hatano, Kojiro Taura, Fumiaki Sato, Masato Narita, Hiromitsu Nagata, Hiroyuki Asechi, Shinji Uemoto, Makoto Kinoshita

Biochimica et Biophysica Acta - Molecular Basis of Disease 1812 巻 ( 11 ) 頁： 1403 - 1411 2011年11月

担当区分：最終著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Elsevier {BV}

BACKGROUND/AIMS: Sept4, a subunit of the septin cytoskeleton specifically expressed in quiescent hepatic stellate cells (HSCs), is downregulated through transdifferentiation to fibrogenic and contractile myofibroblastic cells. Since Sept4(-/-)mice are prone to liver fibrosis, we aimed to identify the unknown molecular network underlying liver fibrosis by probing the association between loss of Sept4 and accelerated transdifferentiation of HSCs. METHODS: We compared the transcriptomes of Sept4(+/+) and Sept4(-/-) HSCs undergoing transdifferentiation by DNA microarray and quantitative reverse transcription polymerase chain reaction (RT-PCR) analysis. Because Dickkopf2 (Dkk2) gene expression is reduced in Sept4(-/-) HSCs, we tested whether supplementing Dkk2 could suppress myofibroblastic transformation of Sept4(-/-) HSCs. We tested the involvement of the canonical Wnt pathway in this process by using a lymphoid enhancer-binding factor/transcription factor-luciferase reporter assay. RESULTS: We observed consistent upregulation of Dkk2 in primary cultured HSCs and in a carbon tetrachloride liver fibrosis in mice, which was decreased in the absence of Sept4. Supplementation with Dkk2 suppressed the induction of pro-fibrotic genes (α-smooth muscle actin and 2 collagen genes) and induced an anti-fibrotic gene (Smad7) in Sept4(-/-) HSCs. In human liver specimens with inflammation and fibrosis, Dkk2 immunoreactivity appeared to be positively correlated with the degree of fibrotic changes. CONCLUSIONS: Pro-fibrotic transformation of HSCs through the loss of Sept4 is, in part, due to reduced expression of Dkk2 and its homologues, and the resulting disinhibition of the canonical Wnt pathway.

DOI： 10.1016/j.bbadis.2011.06.015

Web of Science

PubMed

Submembranous Septins as Relatively Stable Components of Actin-Based Membrane Skeleton 査読有り国際誌

Hagiwara Akari, Tanaka Yasuhiro, Hikawa Rie, Morone Nobuhiro, Kusumi Akihiro, Kimura Hiroshi, Kinoshita Makoto

CYTOSKELETON 68 巻 ( 9 ) 頁： 512 - 525 2011年9月

Ultrastructural localization analysis of septins in mammalian nervous system

Hiroyuki Kurita, Yugo Fukazawa, Natsumi Ageta-Ishihara, Ryuichi Shigemoto, Makoto Kinoshita

Neuroscience Research 71 巻 2011年9月

トランスポートソームの組織化における細胞骨格系の役割査読有り

藤原敬広、木下　専

トランスポートソームの世界-膜輸送研究の源流から未来へ頁： 380 - 386 2011年4月

Septin-dependent microtubule control during mammalian neurite outgrowth 招待有り査読有り

Molecular Biology of the Cell 22 巻 2011年

Role of the Septin Cytoskeleton for the Functional Organization of the Plasma Membrane 招待有り

Makoto Kinoshita

WATER: THE FORGOTTEN BIOLOGICAL MOLECULE 頁： 259 - 267 2011年

Entrapment of intracytosolic bacteria by septin cage-like structures 査読有り国際共著国際誌

Mostowy S, Bonazzi M, Hamon MA, Tham TN, Mallet A, Lelek M, Gouin E, Demangel C, Brosch R, Zimmer C, Sartori A, Kinoshita M, Lecuit M, Cossart P.

Cell Host & Microbe 8 巻 ( 5 ) 頁： 433 - 44 2010年11月

Rho and Anillin-dependent Control of mDia2 Localization and Function in Cytokinesis 査読有り

Molecular Biology of the Cell 21 巻 ( 18 ) 頁： 3193 - 3204 2010年9月

　前のページ - 次のページ　

<木下 専>

論文 - 木下 専

<木下　専>

論文 - 木下　専