政大機構典藏-National Chengchi University Institutional Repository(NCCUR):Item 140.119/95273
English  |  正體中文  |  简体中文  |  Post-Print筆數 : 27 |  Items with full text/Total items : 113325/144300 (79%)
Visitors : 51181615      Online Users : 939
RC Version 6.0 © Powered By DSPACE, MIT. Enhanced by NTU Library IR team.
Scope Tips:
  • please add "double quotation mark" for query phrases to get precise results
  • please goto advance search for comprehansive author search
    •  Adv. Search
    Home ‧ Login ‧ Upload ‧ Help ‧ About ‧ Administer Goto mobile version


    Please use this identifier to cite or link to this item: https://nccur.lib.nccu.edu.tw/handle/140.119/95273


    Title: 確認PIAS1在促進大鼠空間學習與記憶的嶄新角色之探討
    Identification of a novel role of PIAS1 in facilitation of spatial memory formation in rats
    Authors: 劉彥呈
    Contributors: 李小媛
    劉彥呈
    Keywords: 空間學習與記憶
    莫氏水迷津試驗
    西方墨點法
    海馬迴
    Spatial learning and memory
    Morris water maze
    Western blot
    Hippocampus
    PIAS1
    STAT1
    Date: 2009
    Issue Date: 2016-05-09 15:29:54 (UTC+8)
    Abstract: 本實驗室於先前利用莫氏水迷津試驗篩選學習快與學習慢的大白鼠，取出其海馬迴組織並進行聚合酶連鎖反應差異顯示(PCR differential display)，結果顯示學習快與學習慢的大白鼠背側海馬迴之間共有98個cDNA片段有差異表現。把這些cDNA片段進行定序並利用BLAST資料庫比對，其中一個cDNA片段為大白鼠的pias1 [protein inhibitor of activated STAT1 (signal transducer and activator of transcription 1)] 基因。為了瞭解pias1基因的表現是否和空間學習有所關聯，隨機把大白鼠分成兩組，一組為有訓練組別(有空間線索與隱藏式平台)，另一組為無訓練的組別(沒有平台，作為游泳的控制組)同時進行莫氏水迷津學習試驗。試驗完畢，取出海馬迴組織進行即時定量聚合酶連鎖反應與西方墨點法來分析PIAS1的mRNA與蛋白質的表現。結果顯示有水迷津訓練的大白鼠，其PIAS1的mRNA與蛋白質表現皆明顯的高於無訓練的組別。為了更進一步確認PIAS1在空間學習中所扮演的角色，我們利用基因轉染的技術，轉染PIAS1 siRNA至大白鼠海馬迴CA1區域抑制PIAS1的表現。我們發現轉染PIAS1 siRNA至CA1區域會抑制大白鼠在水迷津的行為表現，然而轉染野生型的PIAS1質體基因至CA1區域卻會增進水迷津試驗的學習能力，同時我們也以西方墨點法發現，當轉染PIAS1 siRNA會增加STAT1 Tyr701的磷酸化，而轉染PIAS1 WT則會抑制STAT1 Tyr701的磷酸化。為了探討PIAS1促進記憶形成的分子機制，我們發現當轉染突變型的STAT1 Y701F質體基因至CA1區域，會抑制PIAS1 siRNA所造成記憶的損害。這些實驗結果代表著PIAS1會抑制STAT1 Tyr701的磷酸化，而PIAS1促進記憶的形成可能是藉由抑制STAT1 Tyr701的磷酸化而達成。另外，我們也單獨轉染突變型的STAT1 Y701F質體基因至CA1區域，水迷津實驗結果顯示會促進空間記憶的形成。目前PIAS1在免疫的角色已有許多研究證實，但是本篇研究是第一個提出PIAS1會參與哺乳類動物學習與記憶形成探討。
    Our laboratory has previously identified 98 cDNA fragments by using PCR differential display from rat dorsal hippocampus that are differentially expressed between fast learners and slow learners from the water maze learning task. After sequencing and BLAST analysis, one of these cDNA fragments encodes the rat pias1 [protein inhibitor of activated STAT1 (signal transducer and activator of transcription 1)] gene. In order to determine whether pias1 gene expression is associated with spatial learning, naïve rats were randomly assigned to the trained group (with visual cues and platform been present) and the non-trained group (without the platform as the swimming control). The dorsal hippocampus from these animals was dissected out at the end of the training and was subjected to RNA and protein extraction for real-time PCR and Western blot analysis of PIAS1 expression, respectively. Results revealed that the pias1 mRNA level and protein level was both higher in the hippocampus of trained rats than non-trained rats. To further examine the role of PIAS1 involved in spatial learning and memory, the specific PIAS1 siRNA was used to knockdown the expression of PIAS1 in rat hippocampal CA1 region. We found that transfection of PIAS1 siRNA to the CA1 area impaired water maze performance, whereas transfection of the wild-type PIAS1 DNA plasmid to the CA1 area facilitated water maze performance in rats. Meanwhile, PIAS1 siRNA increased STAT1 phosphorylation at Tyr701 whereas PIAS1 WT decreased STAT1 phosphorylation at this residue. In the examination of molecular mechanism underlying PIAS1-mediated memory facilitation, we have found that transfection of the STAT1 Y701F mutant plasmid antagonized the memory-impairing effect of PIAS1 siRNA, whereas transfection of STAT1 Y701F alone facilitated spatial memory formation. These results together suggest that one of the molecular mechanisms underlying PIAS1-mediated memory facilitation is through decreased STAT1 phosphorylation at Tyr701. All these manipulations did not affect visible platform learning in rats. In addition to the well documented role of PIAS1 in the immune system, here we have been the first to demonstrate a novel role of PIAS1 involved in spatial memory formation in rats.
    Reference: Abdallah B, Hassan A, Benoist C, Goula D, Behr JP, Demeneix BA (1996) A powerful nonviral vector for in vivo gene transfer into the adult mammalian brain: polyethylenimine. Hum Gene Ther 7:1947-1954.
    Aggarwal BB (2003) Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol 3:745-756.
    Amaral DG, Witter MP (1989) The three-dimensional organization of the hippocampal formation: a review of anatomical data. Neuroscience 31:571-591.
    Arora T, Liu B, He H, Kim J, Murphy TL, Murphy KM, Modlin RL, Shuai K (2003) PIASx is a transcriptional co-repressor of signal transducer and activator of transcription 4. J Biol Chem 278:21327-21330.
    Betz A, Lampen N, Martinek S, Young MW, Darnell JE, Jr. (2001) A Drosophila PIAS homologue negatively regulates stat92E. Proc Natl Acad Sci U S A 98:9563-9568.
    Bliss TVP, Gardnerm.Ar (1973) Long-Lasting Potentiation of Synaptic Transmission in Dentate Area of Unanesthetized Rabbit Following Stimulation of Perforant Path. Journal of Physiology-London 232:357-374.
    Bliss TVP, Lomo T (1973) Long-Lasting Potentiation of Synaptic Transmission in Dentate Area of Anesthetized Rabbit Following Stimulation of Perforant Path. Journal of Physiology-London 232:331-356.
    Chung CD, Liao J, Liu B, Rao X, Jay P, Berta P, Shuai K (1997) Specific inhibition of Stat3 signal transduction by PIAS3. Science 278:1803-1805.
    Copeland NG, Gilbert DJ, Schindler C, Zhong Z, Wen Z, Darnell JE, Jr., Mui AL, Miyajima A, Quelle FW, Ihle JN, et al. (1995) Distribution of the mammalian Stat gene family in mouse chromosomes. Genomics 29:225-228.
    Darnell JE, Jr. (1997) STATs and gene regulation. Science 277:1630-1635.
    Darnell JE, Jr., Kerr IM, Stark GR (1994) Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264:1415-1421.
    Davies SN, Collingridge GL (1989) Role of Excitatory Amino-Acid Receptors in Synaptic Transmission in Area Ca1 of Rat Hippocampus. Proceedings of the Royal Society of London Series B-Biological Sciences 236:373-384.
    De-Fraja C, Conti L, Magrassi L, Govoni S, Cattaneo E (1998) Members of the JAK/STAT proteins are expressed and regulated during development in the mammalian forebrain. J Neurosci Res 54:320-330.
    de Kloet ER, Oitzl MS, Joels M (1999) Stress and cognition: are corticosteroids good or bad guys? Trends Neurosci 22:422-426.
    Dupuis S, Jouanguy E, Al-Hajjar S, Fieschi C, Al-Mohsen IZ, Al-Jumaah S, Yang K, Chapgier A, Eidenschenk C, Eid P, Al Ghonaium A, Tufenkeji H, Frayha H, Al-Gazlan S, Al-Rayes H, Schreiber RD, Gresser I, Casanova JL (2003) Impaired response to interferon-alpha/beta and lethal viral disease in human STAT1 deficiency. Nat Genet 33:388-391.
    Duval D, Duval G, Kedinger C, Poch O, Boeuf H (2003) The `PINIT` motif, of a newly identified conserved domain of the PIAS protein family, is essential for nuclear retention of PIAS3L. FEBS Lett 554:111-118.
    Eichenbaum H, Stewart C, Morris RG (1990) Hippocampal representation in place learning. J Neurosci 10:3531-3542.
    Foster TC, Castro CA, Mcnaughton BL (1989) Spatial Selectivity of Rat Hippocampal-Neurons - Dependence on Preparedness for Movement. Science 244:1580-1582.
    Gross M, Yang R, Top I, Gasper C, Shuai K (2004) PIASy-mediated repression of the androgen receptor is independent of sumoylation. Oncogene 23:3059-3066.
    Gross M, Liu B, Tan J, French FS, Carey M, Shuai K (2001) Distinct effects of PIAS proteins on androgen-mediated gene activation in prostate cancer cells. Oncogene 20:3880-3887.
    Hamann SB, Ely TD, Grafton ST, Kilts CD (1999) Amygdala activity related to enhanced memory for pleasant and aversive stimuli. Nat Neurosci 2:289-293.
    Hill AJ, Best PJ (1981) Effects of Deafness and Blindness on the Spatial Correlates of Hippocampal Unit-Activity in the Rat. Experimental Neurology 74:204-217.
    Hou J, Schindler U, Henzel WJ, Ho TC, Brasseur M, McKnight SL (1994) An interleukin-4-induced transcription factor: IL-4 Stat. Science 265:1701-1706.
    Igaz P, Toth S, Falus A (2001) Biological and clinical significance of the JAK-STAT pathway; lessons from knockout mice. Inflamm Res 50:435-441.
    Ihle JN (2001) The Stat family in cytokine signaling. Curr Opin Cell Biol 13:211-217.
    Jackson PK (2001) A new RING for SUMO: wrestling transcriptional responses into nuclear bodies with PIAS family E3 SUMO ligases. Genes Dev 15:3053-3058.
    Jakobs A, Koehnke J, Himstedt F, Funk M, Korn B, Gaestel M, Niedenthal R (2007) Ubc9 fusion-directed SUMOylation (UFDS): a method to analyze function of protein SUMOylation. Nat Methods 4:245-250.
    Jarrard LE (1993) On the Role of the Hippocampus in Learning and Memory in the Rat. Behavioral and Neural Biology 60:9-26.
    Johnson ES (2004) Protein modification by SUMO. Annu Rev Biochem 73:355-382.
    Johnson ES, Gupta AA (2001) An E3-like factor that promotes SUMO conjugation to the yeast septins. Cell 106:735-744.
    Kang Y, He W, Tulley S, Gupta GP, Serganova I, Chen CR, Manova-Todorova K, Blasberg R, Gerald WL, Massague J (2005) Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway. Proc Natl Acad Sci U S A 102:13909-13914.
    Kawai-Kowase K, Kumar MS, Hoofnagle MH, Yoshida T, Owens GK (2005) PIAS1 activates the expression of smooth muscle cell differentiation marker genes by interacting with serum response factor and class I basic helix-loop-helix proteins. Mol Cell Biol 25:8009-8023.
    Kim JJ, Yoon KS (1998) Stress: metaplastic effects in the hippocampus. Trends Neurosci 21:505-509.
    Kipp M, Gohring F, Ostendorp T, van Drunen CM, van Driel R, Przybylski M, Fackelmayer FO (2000) SAF-Box, a conserved protein domain that specifically recognizes scaffold attachment region DNA. Mol Cell Biol 20:7480-7489.
    Kotaja N, Karvonen U, Janne OA, Palvimo JJ (2002) PIAS proteins modulate transcription factors by functioning as SUMO-1 ligases. Mol Cell Biol 22:5222-5234.
    Levy DE, Darnell JE, Jr. (2002) Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol 3:651-662.
    Liu B, Gross M, ten Hoeve J, Shuai K (2001) A transcriptional corepressor of Stat1 with an essential LXXLL signature motif. Proc Natl Acad Sci U S A 98:3203-3207.
    Liu B, Liao J, Rao X, Kushner SA, Chung CD, Chang DD, Shuai K (1998) Inhibition of Stat1-mediated gene activation by PIAS1. Proc Natl Acad Sci U S A 95:10626-10631.
    Liu B, Mink S, Wong KA, Stein N, Getman C, Dempsey PW, Wu H, Shuai K (2004) PIAS1 selectively inhibits interferon-inducible genes and is important in innate immunity. Nat Immunol 5:891-898.
    Liu B, Yang R, Wong KA, Getman C, Stein N, Teitell MA, Cheng G, Wu H, Shuai K (2005) Negative regulation of NF-kappaB signaling by PIAS1. Mol Cell Biol 25:1113-1123.
    Liu B, Yang Y, Chernishof V, Loo RR, Jang H, Tahk S, Yang R, Mink S, Shultz D, Bellone CJ, Loo JA, Shuai K (2007) Proinflammatory stimuli induce IKKalpha-mediated phosphorylation of PIAS1 to restrict inflammation and immunity. Cell 129:903-914.
    Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25:402-408.
    Long J, Wang G, Matsuura I, He D, Liu F (2004) Activation of Smad transcriptional activity by protein inhibitor of activated STAT3 (PIAS3). Proc Natl Acad Sci U S A 101:99-104.
    Long J, Matsuura I, He D, Wang G, Shuai K, Liu F (2003) Repression of Smad transcriptional activity by PIASy, an inhibitor of activated STAT. Proc Natl Acad Sci U S A 100:9791-9796.
    Lungwitz U, Breunig M, Blunk T, Gopferich A (2005) Polyethylenimine-based non-viral gene delivery systems. Eur J Pharm Biopharm 60:247-266.
    Martin S, Nishimune A, Mellor JR, Henley JM (2007) SUMOylation regulates kainate-receptor-mediated synaptic transmission. Nature 447:321-325.
    Martres MP, Demeneix B, Hanoun N, Hamon M, Giros B (1998) Up- and down-expression of the dopamine transporter by plasmid DNA transfer in the rat brain. Eur J Neurosci 10:3607-3616.
    McBride KM, Reich NC (2003) The ins and outs of STAT1 nuclear transport. Sci STKE 2003:RE13.
    McGaugh JL, Cahill L, Roozendaal B (1996) Involvement of the amygdala in memory storage: interaction with other brain systems. Proc Natl Acad Sci U S A 93:13508-13514.
    McNaughton BL, Barnes CA, Meltzer J, Sutherland RJ (1989) Hippocampal Granule Cells Are Necessary for Normal Spatial-Learning but Not for Spatially-Selective Pyramidal Cell Discharge. Exp Brain Res 76:485-496.
    Mohr SE, Boswell RE (1999) Zimp encodes a homologue of mouse Miz1 and PIAS3 and is an essential gene in Drosophila melanogaster. Gene 229:109-116.
    Morris RG, Garrud P, Rawlins JN, O`Keefe J (1982) Place navigation impaired in rats with hippocampal lesions. Nature 297:681-683.
    Moser E, Moser MB, Andersen P (1993) Spatial learning impairment parallels the magnitude of dorsal hippocampal lesions, but is hardly present following ventral lesions. J Neurosci 13:3916-3925.
    Mui AL (1999) The role of STATs in proliferation, differentiation, and apoptosis. Cell Mol Life Sci 55:1547-1558.
    Okeefe J, Dostrovs.J (1971) Hippocampus as a Spatial Map - Preliminary Evidence from Unit Activity in Freely-Moving Rat. Brain Research 34:171-&.
    Okuma T, Honda R, Ichikawa G, Tsumagari N, Yasuda H (1999) In vitro SUMO-1 modification requires two enzymatic steps, E1 and E2. Biochem Biophys Res Commun 254:693-698.
    Park OK, Schaefer TS, Nathans D (1996) In vitro activation of Stat3 by epidermal growth factor receptor kinase. Proc Natl Acad Sci U S A 93:13704-13708.
    Paxinos G. WC (1986) The rat brain in stereotaxic coordinates, Orlando, Academic Press.
    Rogers RS, Horvath CM, Matunis MJ (2003) SUMO modification of STAT1 and its role in PIAS-mediated inhibition of gene activation. J Biol Chem 278:30091-30097.
    Sachdev S, Bruhn L, Sieber H, Pichler A, Melchior F, Grosschedl R (2001) PIASy, a nuclear matrix-associated SUMO E3 ligase, represses LEF1 activity by sequestration into nuclear bodies. Genes Dev 15:3088-3103.
    Sachsenmaier C, Sadowski HB, Cooper JA (1999) STAT activation by the PDGF receptor requires juxtamembrane phosphorylation sites but not Src tyrosine kinase activation. Oncogene 18:3583-3592.
    Sarazin M, Deweer B, Merkl A, Von Poser N, Pillon B, Dubois B (2002) Procedural learning and striatofrontal dysfunction in Parkinson`s disease. Mov Disord 17:265-273.
    Schenk F, Morris RG (1985) Dissociation between components of spatial memory in rats after recovery from the effects of retrohippocampal lesions. Exp Brain Res 58:11-28.
    Schindler C, Levy DE, Decker T (2007) JAK-STAT signaling: from interferons to cytokines. J Biol Chem 282:20059-20063.
    Scoville WB, Milner B (1957) Loss of recent memory after bilateral hippocampal lesions. J Neurol Neurosurg Psychiatry 20:11-21.
    Shuai K (2000) Modulation of STAT signaling by STAT-interacting proteins. Oncogene 19:2638-2644.
    Shuai K (2006) Regulation of cytokine signaling pathways by PIAS proteins. Cell Res 16:196-202.
    Shuai K, Liu B (2003) Regulation of JAK-STAT signalling in the immune system. Nat Rev Immunol 3:900-911.
    Shuai K, Liu B (2005) Regulation of gene-activation pathways by PIAS proteins in the immune system. Nat Rev Immunol 5:593-605.
    Song L, Bhattacharya S, Yunus AA, Lima CD, Schindler C (2006) Stat1 and SUMO modification. Blood 108:3237-3244.
    Squire LR (1992) Memory and the Hippocampus - a Synthesis from Findings with Rats, Monkeys, and Humans. Psychological Review 99:195-231.
    Squire LR, Alvarez P (1995) Retrograde amnesia and memory consolidation: a neurobiological perspective. Curr Opin Neurobiol 5:169-177.
    Strehlow I, Schindler C (1998) Amino-terminal signal transducer and activator of transcription (STAT) domains regulate nuclear translocation and STAT deactivation. J Biol Chem 273:28049-28056.
    Taube JS, Kesslak JP, Cotman CW (1992) Lesions of the rat postsubiculum impair performance on spatial tasks. Behav Neural Biol 57:131-143.
    Teyler TJ, Discenna P (1987) Long-Term Potentiation. Annual Review of Neuroscience 10:131-161.
    Tsai KJ, Chen SK, Ma YL, Hsu WL, Lee EH (2002) sgk, a primary glucocorticoid-induced gene, facilitates memory consolidation of spatial learning in rats. Proc Natl Acad Sci U S A 99:3990-3995.
    Tsien JZ, Huerta PT, Tonegawa S (1996) The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory. Cell 87:1327-1338.
    Tussie-Luna MI, Bayarsaihan D, Seto E, Ruddle FH, Roy AL (2002) Physical and functional interactions of histone deacetylase 3 with TFII-I family proteins and PIASxbeta. Proc Natl Acad Sci U S A 99:12807-12812.
    Ungureanu D, Vanhatupa S, Gronholm J, Palvimo JJ, Silvennoinen O (2005) SUMO-1 conjugation selectively modulates STAT1-mediated gene responses. Blood 106:224-226.
    Ungureanu D, Vanhatupa S, Kotaja N, Yang J, Aittomaki S, Janne OA, Palvimo JJ, Silvennoinen O (2003) PIAS proteins promote SUMO-1 conjugation to STAT1. Blood 102:3311-3313.
    Vanhatupa S, Ungureanu D, Paakkunainen M, Silvennoinen O (2008) MAPK-induced Ser727 phosphorylation promotes SUMOylation of STAT1. Biochem J 409:179-185.
    Wen Z, Zhong Z, Darnell JE, Jr. (1995) Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell 82:241-250.
    Yamamoto H, Ihara M, Matsuura Y, Kikuchi A (2003) Sumoylation is involved in beta-catenin-dependent activation of Tcf-4. EMBO J 22:2047-2059.
    Zola-Morgan S, Squire LR, Amaral DG (1986) Human amnesia and the medial temporal region: enduring memory impairment following a bilateral lesion limited to field CA1 of the hippocampus. J Neurosci 6:2950-2967.
    Description: 碩士
    國立政治大學
    生命科學研究所
    96754001
    Source URI: http://thesis.lib.nccu.edu.tw/record/#G0096754001
    Data Type: thesis
    Appears in Collections:[Graduate Institute of Neuroscience] Theses

    Files in This Item:

    File SizeFormat
    index.html0KbHTML2360View/Open


    All items in 政大典藏 are protected by copyright, with all rights reserved.


    社群 sharing

    著作權政策宣告 Copyright Announcement
    1.本網站之數位內容為國立政治大學所收錄之機構典藏，無償提供學術研究與公眾教育等公益性使用，惟仍請適度，合理使用本網站之內容，以尊重著作權人之權益。商業上之利用，則請先取得著作權人之授權。
    The digital content of this website is part of National Chengchi University Institutional Repository. It provides free access to academic research and public education for non-commercial use. Please utilize it in a proper and reasonable manner and respect the rights of copyright owners. For commercial use, please obtain authorization from the copyright owner in advance.

    2.本網站之製作，已盡力防止侵害著作權人之權益，如仍發現本網站之數位內容有侵害著作權人權益情事者，請權利人通知本網站維護人員(nccur@nccu.edu.tw)，維護人員將立即採取移除該數位著作等補救措施。
    NCCU Institutional Repository is made to protect the interests of copyright owners. If you believe that any material on the website infringes copyright, please contact our staff(nccur@nccu.edu.tw). We will remove the work from the repository and investigate your claim.
    DSpace Software Copyright © 2002-2004  MIT &  Hewlett-Packard  /   Enhanced by   NTU Library IR team Copyright ©   - Feedback