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博碩士論文 etd-0717102-120610 詳細資訊
Title page for etd-0717102-120610
論文名稱
Title
APP結合蛋白質1與脯胺酸異構酶Pin1對beta-Amyloid前驅蛋白質的交互作用與調節
Interaction and Regulation of beta-Amyloid Precursor Protein by APPBP1 and Pin1
系所名稱
Department
畢業學年期
Year, semester
語文別
Language
學位類別
Degree
頁數
Number of pages
126
研究生
Author
指導教授
Advisor
召集委員
Convenor
口試委員
Advisory Committee
口試日期
Date of Exam
2002-06-14
繳交日期
Date of Submission
2002-07-17
關鍵字
Keywords
交互作用、調節、蛋白質
pin1, regulation, interacton, APPBP1, beta-amyloid precursor protein
統計
Statistics
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The thesis/dissertation has been browsed 5721 times, has been downloaded 12235 times.
中文摘要
b-Amyloid (Ab) 所形成的senile plaques被認為是造成Alzheimer’s disease (AD) 的原因之一,也是AD之一個重要病理徵象,但目前對於Ab的沈積與Alzheimer’s disease之間的關係仍是不完全清楚的。Ab來自一個前驅蛋白質,稱為b-Amyloid precursor protein (APP) ,當APP經b secretases和g secretases切割後,可釋出Ab,然而APP的正常生理功能亦尚未定論。結構分析APP為type I transmembrane protein,N-terminus朝向細胞膜外,含有兩個glycosylation sites,可經由轉譯後修飾的作用進行N-glycosylation及O-glycosylation,此過程與APP的maturation有關;C-terminus則位於細胞膜內,不但含有三個可被磷酸化的位置 (Thr654,Ser655及Thr668,數字參照APP695) ,並且包含數個具功能性的保留性序列,這些保留性序列已被證明可與特定的蛋白質進行交互作用,因而APP的C-terminus (APPC) 被認為可能與細胞訊息傳遞有關。APP binding protein 1 (APPBP1) 可與APP的C-terminus結合,研究指出APPBP1是S-M checkpoint之調節者,為參與細胞分裂不可缺少的因子,然而目前對APPBP1在細胞內的分佈及其生理功能仍不完全清楚。蛋白質的磷酸化作用常會影響蛋白質的構形與其他分子的結合能力。研究指出APPC的三個磷酸化位置以Thr668被磷酸化後所造成構形的改變最為顯著,這是因為Pro669之cis / trans isomerization所造成的構形上的影響;此生理意義亦待進一步的研究。Ser / Thr Pro motif為Cdc2在受質上所磷酸化的位置,而APPC之Thr668及Pro669已被證明為Cdc2 的磷酸化位置。加上目前研究顯示在Alzheimer’s disease的腦部組織中發現有不正常的mitotic events產生,伴隨大量mitotic proteins表現增加的情形,其中Cdc2亦不正常地被活化在AD brain,而被認為與神經元細胞的死亡和AD的致病機制可能有密切的關係。另一方面Cdc2磷酸化Thr668對於調控APP正常的生理功能與其代謝亦可能扮演重要的角色,但其產生何種訊息傳導仍是未知的。Pin1,是一個重要的mitotic regulator,本實驗室初步證明Pin1只能與mitotic phase時的APP進行interaction (Kd為20 nM) 。由於Pin1為peptidyl-prolyl cis / trans isomerases,其與APP的結合意涵著某種生化活性的調控。在本研究中我們獲得以下結果: (1) APPC及APPBP1皆可表現在細胞質與細胞膜: (2) 無論是in vivo或in vitro,APPC皆可與APPBP1結合;(3) Thr668為APP唯一之Cdc2 phosphorylation site;(4) 當APPBP1結合至APPC時影響Cdc2磷酸化APPC;(5) APP之Thr668的磷酸化可減低與APPBP1或Pin1的結合;(6) APPC為caspase 3的受質;(7) APPC之Thr668磷酸化調控caspase 3 activity;(8) APPBP1或Pin1與APPC的結合可調控caspase 3 activity。



Abstract
b-amyloid is derived from amyloid precursor protein (APP) and tightly associated with the pathogenesis of Alzheimer’s disease (AD). Structurally, APP belongs to type I transmembrane protein family and is composed of a large glycosylated extracellular component, a single membrane-spanning region, and a short cytoplasmic domain. Although physiological function of APP remains unclear, the proteolytic processing of APP by b secretase and g secretase gives rise to the production and secretion of b-amyloid. The C-terminus of APP is believed to participate in the intracellular trafficking of APP and signal transduction via interacting with adaptors and signaling proteins, respectively. Three phosphorylation sites (Thr654, Ser655 and Thr668, numbering for APP695 isoform) and several functional motifs in the cytoplasmic domain of APP have been identified and demonstrated that the phosphorylation can indeed affect APP metabolism including: the rate of secretion, endocytosis and b-amyloid production. In this study, we focused on how APP binding protein1 and the phosphorylation affect on APP metabolism. The reasons are as following: (1) Among many APP associated proteins, APP binding protein 1 (APPBP1) is involved in S-M checkpoint regulation. (2) Recent evidence indicates that aberrantly activation of mitotic events may play an important role in development of AD. Since progression through mitosis is regulated by Cdc2 that has been demonstrated to phosphorylate APP on Thr668-Pro669, the phosphorylation of APP at Thr668 may play the important role in regulating APP metabolism and may also relate to AD development. (3) Moreover, protein phosphorylation induces the conformational change and affects the protein- protein interaction. Phosphorylation of Ser / Thr-Pro motif is a central mechanism controlling progression of the cell cycle, including mitosis. Proline residues provide a potential backbone switch in the polypeptide chain controlled by the cis / trans isomerization. Pin1 is an important mitotic regulator and a highly specific peptidyl-prolyl cis / trans isomerases (PPIase) that catalyzes the isomerization of phosphorylated Ser / Thr-Pro bonds. Our unpublished data have shown that Pin1 can bind to the phosphorylated Thr668-Pro669 APP peptide with high affinity (20 nM) that suggested that Pin1 may interact and regulate mitotic APP. Taken together, these data suggested that the interaction of APP and APPBP1 or Pin1 may affect the APP metabolism and its physiological function. This study investigated the hypothesis above and revealed includes the following results (i) the subcellular localization of the C-terminus of APP and APPBP1; (ii) the interaction between APPBP1 and the C-terminus of APP in vivo and in vitro; (iii) Thr668 of APP is the Cdc2 phosphorylation site; (iv) the binding of APPBP1 to the C-terminus of APP reduces the phosphorylation of APP by Cdc2; (v) the phosphorylation at Thr668 can abolish the interaction between APPBP1 and the C-terminus of APP; (vi) the C-terminus of APP is one of the caspase 3 targets; (vii) the phosphorylation of APP at Thr668 also reduces the caspase 3 activity forward to the C-terminus of APP cleavage; (viii) both APPBP1 and Pin1 can inhibit the C-terminus of APP cleavage by caspase 3 that suggested two novel mechanisms to regulate APP metabolism.

目次 Table of Contents
目錄

中文摘要…………………………………………………….…………..…i
英文摘要…………………………………………………………..……....iv
英文縮寫表………………….………………….………………..…..…...vii
緒論…………………………………….………………….………………1
材料與方法……………………………….………………………………13
結果…………………….………………….………………….…………..46
討論…………………………..……………….………………….……….56
參考文獻…………………….……………….…………………………...63
圖解……………………………………………….………………………77
圖……………………….…………………………………………………85
表……………………….……………………….…..…………………..104
附錄……………………….……………………….……………………106

參考文獻 References
Ando, K., Iijima, K.-i., Elliott, J. I., Kirino, Y. and Suzuki, T. (2001) Phosphorylation-dependent Regulation of the Interaction of Amyloid Precursor Protein with Fe65 Affects the Production of beta -Amyloid. J. Biol. Chem. 276, 40353-40361.
Aplin, E. E., Gibb, G. M., Jacobsen, J. S., Gallo, J.-M. and Anderton, B. H. (1996) In vitro phosphorylation of the cytoplasmic domain of the amyloid precursor protein by glycogen synthase kinase-3 beta. J. Neurochem. 67, 699-707.
Bertrand, E., Brouillet, E., Caille, I., Bouillot, C., Cole, G. M., Prochiantz, A. and Allinquant, B. (2001) A short cytoplasmic domain of the amyloid precursor protein induces apoptosis in vitro and in vivo. Mol Cell Neurosci. 18, 503-511.
Borg, J. P., Ooi J., Levy, E. and Margolis, B. (1996) The Phosphotyrosine interaction domains of X11 and Fe65 binding to distinct sites on the YENPTY motif of Amyloid Precursor Protein. Mol. Cell Biol. 16, 6229-6241.
Borg, J. P., Yang, Y., De Taddeo-Borg, M., Margolis, B. and Turner, R. S. (1998) The X11a Protein Slows Cellular Amyloid Precursor Protein Processing and Reduces Ab40 and Ab42 Secretion. J Biol Chem. 273, 14761-14766.
Chen, Y., McPhie, D. L., Hirschberg, J.and Neve, R. L. (2000) The amyloid precursor protein-binding protein APP-BP1 drives the cell cycle through the S-M checkpoint and causes apoptosis in neurons. J. Biol. Chem. 275, 8929-8935.
Chow, N., Korenberg, J. R., Chen, X.-N. and Neve, R. L. (1996) APP-BP1, a Novel Protein That Binds to the Carboxyl-terminal Region of the Amyloid Precursor Protein. J. Biol. Chem. 271, 1441339-11346.
Cohen G. M. (1997) Caspases : the executioners of apopotosis. J. Biochem. 326, 1-16.
Copani, A., Uberti, D., Sortino, M. A., Bruno, V., Nicoletti, F. and Memo, M. (2001) Activation of cell-cycle-associated proteins in neuronal death : a mandatory or dispensable path ? Trends Neurosci. 24, 25-31.
Dhavan, R. and Tsai, L. H. (2001) A DECADE OF CDK5. Nat Rev Mol Cell Biol. 2, 749-759.
Duilio, A., Faraonio, R., Minopoli, G., Zambrano, N. and Russo, T. (1998) Fe65L2 : a new member of the Fe65 protein family interacting with the intracellular domain of the Alzheimer’s beta-amyloid precursor protein. Biochem. J. 330, 513-519.
Dyrks, T., Weidemann, A., Multhaup, G., Salbaum, J. M., Lemaire, H.-G., Kang, J., Muller-Hill, B., Masters, C. L. and Beyreuther, K. (1988) Identification, transmembrane orientation and biogenesis of the amyloid A4 precursor of Alzheimer's disease. EMBO J. 7, 949-957.
Fiore, F., Zambrano, N., Minopoli, G., Donini, V., Duilio, A. and Russo, T. (1995) The Regions of the Fe65 Protein Homologous to the Phosphotyrosine Interaction / Phosphotyrosine Binding Domain of Shc Bind the Intracellular Domain of the Alzheimer's Amyloid Precursor Protein. J. Biol. Chem. 270, 30853-30856.
Gandy, S., Czernik, A. J. and Greengard, P. (1988) Phosphorylation of Alzheimer disease amyloid precursor peptide by protein kinase C and Ca2+ / calmodulin-dependent protein kinase II. Proc Natl Acad Sci U.S.A. 16, 6218-6221.
Gassen, G. V., Annaert, W. and Broeckhoven, C. V. (2000) Bingding Partners of Alzheimer’s Disease Proteins : Are They Physiologically Relevant?Neurobiol Dis. 7, 135-151.
Gervais, F. G., Xu, D., Robertson, G. S., Vaillancourt J.P., Zhu, Y., Huang, J., LeBlanc, A., Smith, D., Rigby, M., Shearman, M. S., Clarke, E.E., Zheng, H., Van Der Ploeg, L.H., Ruffolo, S.C., Thornberry, N.A., Xanthoudakis, S., Zamboni, R.J., Roy, S. and Nicholson, D.W. (1999) Involvement of caspases in proteolytic cleavage of Alzheimer's amyloid-beta precursor protein and amyloidogenic A beta peptide formation. Cell, 97, 395-406.
Golde, T. E., Eckman, C. B. and Younkin, S. G. (2000) Biochemical detection of Ab isoforms : implications of pathogenesis diagnosis, and treatment of Alzheimer’s disease. Biochim Biophys Acta. 1502, 172-187.
Golde, T. E., Eckman, C. B. and Younkin, S. G. (2000) Biochemical detection of Abeta isoforms: implications for pathogenesis, diagnosis, and treatment of Alzheimer's disease. Biochim Biophys Acta. 1502, 172-187.
Greengard, P. (1994) Cell cycle-dependent regulation of the phosphorylation and metabolism of the Alzheimer amyloid precursor protein. EMBO J. 13, 1114-1122.
Guenette, S. Y., Chen, J., Jondro, P. D. and Tanzi, R. E. (1996) Association of a novel human FE65-like protein with the cytoplasmic domain of the b-amyloid precursor protein. Proc. Natl. Acad. Sci. U. S. A. 93, 10832-10837.
Homayouni, R., Rice, D. S., Sheldon, M. and Curran, T. (1999) Disabled-1 Binds to the Cytoplasmic Domain of Amyloid Precursor-Like Protein 1. J. Neurosci. 19, 7507-7515.
Howell, B. W., Gertler, F. B. and Cooper, J. A. (1997) Mouse disabled (mDab1) : a Src binding protein implicated in neuronal development. EMBO J. 16, 121-132.
Hunter, T. (1998) Prolyl isomerases and nuclear function. Cell 92, 141-143.
Iijima, K. Ando, K., Takeda, S., Satoh, Y., Itohara, S., Greengard, P., Kirino, Y., Nairn, A. C. and Suzuki, T. (2000) Neuron-specific phosphorylation of Alzheimer's beta-amyloid precursor protein by cyclin-dependent kinase 5. J. Neurochem. 75, 1085-1091.
Isohara, T., Horiuchi, A., Watanabe, T., Ando, K., Czernik, A. J., Uno, I., Greengard, P., Nairn, A. C. and Suzuki T. (1999) Phosphorylation of the cytoplasmic domain of Alzheimer's beta-amyloid precursor protein at Ser655 by a novel protein kinase. Biochem Biophys Res Commun. 258, 300-305.
Kang, J., Lemaire, H.-G., Unterback, A., Salbaum, J. M., Masters, C. L., Grezeschik, K. H., Multhaup, G., Beyreuther, K. and Muller-Hill, B. (1987) The precursor of Alzheimer disease amyloid A4 protein resembles a cell-surface receptor. Nature 325, 733-736.
Kuhn, H. G., Palmer, T. D. and Fuchs, E. (2001) Adult nerogenesis : a compensatory mechanism for neuronal damage. Eur Arch Psychiatry Clin Neurosci. 251, 152-158.
Lai, A., Sisodia, S. S. and Trowbridge, I. S. (1995) Characterization of Sorting Signals in the b-Amyloid Precursor Protein Cytoplasmic Domain. J.Biol Chem. 270, 3565-3673.
Lang, J., Nishimoto, I., Okamoto, T., Sadoul, K., Regazzi, R., Kiraly, K., Weller, U. and Wollheim, C. B. (1995) Direct control of exocytosis by receptor activation of the heterotrimeric GTPases Gi and Go or the expression of their active G-subunits. EMBO J. 14, 3635-3644.
Lu, D. C., Rabizadh, S., Chandra, S., Shayya, R. F., Ellerby, L. M., Ye, X., Salvesen, G. Y., Koo, E. H. and Bredesen, D. E. (2000) A second cytotoxic proteolytic peptide derived from amyloid b-protein precusor. Nat. Med. 6, 397-404.
Lu, K. P. (2000) Phosphorylation-dependent prolyl isomerization : a novel cell cycle regulatory mechanism. Pro Cell Cycle Res. 4, 83-96.
Lu, K. P., Hanes, S. D. and Hunter, T. (1996) A human peptidyl-prolyl isomerase essential for regulation of mitosis. Nature 380, 544-547.
Lu, K. P., Liou, Y. C. and Zhou, X. Z. (2002) Pinning down proline-directed phosphorylation signaling. Trends Cell Biol. 12, 164-172.
Maccioni, R. B., Munoz, J. P. and Barbeito, L. (2001) The molecular bases of Alzheimer's disease and other neurodegenerative disorders. Arch Med Res. 32, 367-381.
McLoughlin, D. M. and Miller, C. C. (1996) The intracellular cytoplasmic domain of the Alzheimer’s disease amyloid precursor protein interacts with phosphotyrosine-binding domain proteins in the yeast two-hybrid system. FEBS Lett. 397, 197-220.
McShea, A., Harris, P. L. R., Webster, K. R. Wahl, A. F. and Smith, M. A. (1997) Abnormal expression of the cell cycle regulator P16 and Cdk4 in Alzheimer’s disease. Am. J. Path. 150, 1933-1939.
Michel, P. P., Lambeng, N. and Ruberg, M. (1999) Neuropharmacologic aspects of apoptosis : significance for neurodegenerative diseases. Clin Neuropharmacol. 22, 137-150.
Mills, J. and Reinger, P. B. (1999) Regulation of Amyloid Precursor Protein Cleavage. J. Neurochem. 72, 443-460.
Nagy, Z. (2000) Cell cycle regulatory failure in neurons : causes and consequences. Neurobiol Aging. 21, 761-769.
Nagy, Z., Esiri, M. M. and Smith, A. D. (1998) The cell division cycle and the pathophysiology of Alzheimer’s disease. Neurosciece 87, 731-739.
Nagy, Z., Esirs, M. M. and Smith, A. D. (1997) Expression of cell division markers in the hippocampus in Alzheimer’s disease and other neurodegenerative conditions. Acta Neuropath. 93, 294-301.
Neve, R. L., McPhine, D. L. and Chen, Y. (2000) Alzheimer’s disease : a dysfunction of the amyloid precursor protein. Brain Res. 886, 54-66.
Nicholson, D. W., Ali, A., Thornberry, N. A., Vaillancourt, J. P., Ding, C. K., Gallant, M., Gareau, Y., Griffin, P. R., Labelle, M. and Lazebnik, Y. A. (1995) Identification and inhibition of the ICE / CED-3 protease necessary for mammalian apoptosis. Nature 376, 37-43.
Nishimura, I., Uetsuki, T., Kuwako, K., Hara, T., Kawakami, T., Aimoto, S. and Yoshikawa, K. (2002) Cell death induced by a caspase-cleaved transmembrane fragment of the Alzheimer amyloid precursor protein. Cell Death Differ. 9, 199-208.
Nurse, P. (1994) Ordering S phase and M phase. Cell 79, 547-550.
Oishi, M., Nairn, A. C., Czernik, A. J., Lim, G. S., Isohara, T., Gandy, S. E., Greengard, P. and Suzuki, T. (1997) The cytoplasmic domain of Alzheimer's amyloid precursor protein is phosphorylated at Thr654, Ser655, and Thr668 in adult rat brain and cultured cells. Mol Med. 3, 111-123.
Okamoto, T., Takeda, S., Murayama, Y., Ogata, E. and Nishimoto, I. (1995) Ligand-dependent G protein coupling function of amyloid transmembrane precursor. J. Biol. Chem. 270, 4205-4208.
Raina, A. K., Zhu, X. Monteiro, M., Takeda, A. and Smith, M. A. (2000) Abortive oncogeny and cell cycle-mdiated events in Alzheimer’s disease. Prog Cell Cycle Res. 4, 235-242.
Ramelot, T. A. and Nicholson, L. K. (2001) Phosphorylation-induced structural changes in the amyloid precursor protein cytoplasmic tail detected by NMR. J Mol Biol. 307, 871-844.
Ramelot, T. A., Gentile, L. N. and Nicholson, L. K. (2000) Transient structure of the amyloid precursor protein cytoplasmic tail indicates preordering of structure for binding to cytosolic factors. Biochemistry 39, 2714-2725.
Rippmann, J. F., Hobbie, S., Daiber, C., Guilliard B., Bauer, M., Birk, J., Nar, H., Garin-Chesa, P. and Rettig, W. J. (2000) Phosphorylation-dependent proline isomerization catalyzed by Pin1 is essential for tumor cell survival and entry into mitosis. Cell Growth Differ. 11, 409-416.
Ross, M. E. (1996) Cell dividion and the nervous system : regulating the cycle from neural differentiation to death. Trends Neurosci. 19, 62-68.
Roth, K. A. (2001) Caspases, apoptosis, and Alzheimer disease : causation, correlation, and confusion. J Neuropathol Exp Neurol. 60, 829-838.
Sabo, S. L., Lanier, L. M., Ikin, A. F., Khorkova, O., Sahasrabudhe, S., Greengard, P. and Buxbaum, J. D. (1999) . Regulation of beta -Amyloid Secretion by FE65, an Amyloid Protein Precursor-binding Protein. J. Biol. Chem. 274, 7952-7957.
Sastre, M., Turner, R. S. and Levy, E. (1998) X11 Interaction with b-Amyloid Precursor Protein Modulates Its Cellular Stabilization and Reduces Amyloid b-Protein Secretion. J. Biol. Chem. 273, 22351-22357.
Schubert, W., Prior, R., Weidemann, A., Dircksen, H., Multhaup, G., Masters, C. L. and Beyreuther, K. (1991) Localization of Alzheimer A4 amyloid precursor protein at central and peripheral synaptic sites. Brain Res., 563, 184-194.
Shen, M., Stukenberg, P. T., Kirschner, M. W. and Lu, K. P. (1998) The essential mitotic peptidyl-prolyl isomerase Pin1 binds and regulates mitotsis-specific phosphoproteins. Genes Dev. 12, 706-720.
Shinomyia, N. (2001) New concepts in radiation-induced apoptosos : premitotic apoptosis and postmitotic apoptosis. J Cell Mol Med. 5, 240-253.
Soriano, S., Lu, D. C., Chandra, S., Pietrzik, C. U. and Koo, E. H. (2001) The amyloidogenic pathway of amyloid precursor protein (APP) is independent of its cleavage by caspases. J Biol Chem. 276, 29045-29050.
Springer, J. E., Nottingham, S. A., McEwen, M. L., Azbill, R. D. and Jin, Y. (2001) Caspase-3 apoptotic signaling following injury to the central nervous system. Clin Chem Lab Med. 39, 299-307.
Suzuki, T., Nairn, A. C., Gandy, S. E. and Greengard, P. (1992) Phosphorylation of Alzheimer amyloid precursor protein by protein kinase C. Neuroscience 48, 755-761.
Suzuki, T., Oishi, M., Marshak, D. R., Czernik, A. J., Nairn, A. C., Tanahashi, H. and Tabira, T. (1999) X11L2, a new member of the X11 protein family, interacts with Alzheimer's beta-amyloid precursor protein. Biochem. Biophys. Res. Commun. 255, 663-667.
Suzuki, T., Oishi, M., Marshak, D. R., Czernik, A. J., Nairn, A. C. and Greengard, P. (1994) Cell cycle-dependent regulation of the phosphorylation and metabolism of the Alzheimer amyloid precursor protein. EMBO J. 13, 1114-1122.
Tanahashi, H. and Tabira, T. (1999) Molecular cloning of human Fe65L2 and its interaction with the Alzheimer's beta-amyloid precursor protein. Neurosci Lett. 261, 143-146.
Tanahashi, H. and Tabira, T. (1999) X11L2, a new member of the X11 protein family, interacts with Alzheimer's beta-amyloid precursor protein. Biochem Biophys Res Commun. 255, 663-667.
Tewari, M., Quan, L. T., O’Rourke, K., Desnoyers, S., Zeng, Z., Beidler, D. R., Poirier, G. G., Salvesen, G. S. and Dixit, V. M. (1995) Yama / CPP32 beta, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly (ADP-ribose) polymerase. Cell 81, 801-809.
Tomita, S., Ozaki, T., Taru, H., Oguchi, S., Takeda, S., Yagi, Y., Sakiyama, S., Kirino, Y. and Suzuki, T. (1999) Interaction of a Neuron-specific Protein Containing PDZ Domains with Alzheimer’s Amyloid Precursor Protein. J. Biol. Chem. 274, 2243-2254.
Trommsdorff, M., Borg, J. P., Margolis, B. and Herz, J. (1998) Interaction of Cytosolic Adaptor Proteins with Neuronl Apoliporotein E Receptors and the Amyloid Precursor Protein. J. Biol. Chem. 273, 33556-33560.
Vincent, I., Jicha, G., Rosado, M. and Dickson D. W. (1997) Aberrant expression of mitotic Cdc2 / cyclin B1 kinase in degenerating neurons of Alzheimer’s disease brain. J Neurosci. 17, 3588-3598.
Watanabe, T., Sukegawa, J., Sukegawa, I., Tomita, S., Iijima, K.-i., Oguchi, S., Suzuki, T., Nairn, A. C. and Greengard, P. (1999) A 127-kDa Protein (UV-DDB) Binds to the Cytoplasmic Domain of the Alzheimer's Amyloid Precursor Protein. J Neurochem. 72, 549-556.
Winkler, K. E., Swenson, K. I., Kornbluth, S. and Means, A. R. (2000) Requirement of the prolyl isomerase Pin1 for the replication checkpoint. Science 287, 1644-1647.
Yaffe, M. B., Schutkowski, M., Shen, M., Zhou, X. Z., Stukenberg, P. T., Rahfeld, J. U., Xu, J., Kuang, J., Kirschner, M. W., Fischer, G., Cantlyey, L. C. and Lu. K. P. (1997) Sequence-specific and phosphorylation-dependent proline isomerization: a potential mitotic regulatory mechanism. Science 278, 1957-1960.
Yoshikawa, K. (2000) Cell cycle regulators in neural stem cells and postmitotic neurons. Neurosci Res. 37, 1-14.
Zheng, P., Eastman, J., Vande Pol, S. and Pimplikar, S. W. (1998) PAT1, a microtubule-interacting protein, recognizes the basolateral sorting signal of amyloid precursor protein. Proc. Natl. Acas Sci. U.S.A. 95, 14745-14750.
Zhou, X. Z., Lu, P. J. Wulf, G. and Lu, K. P. (1999) Phosphorylation-dependent prolyl isomerization : a novel signaling regulatory mechanism. Cell Mol Life Sci. 56, 788-806.
Zupanc, G. K. (1999) Neurogenesis, cell death and regeneration in the adult gymnotiform brain. J. Exp Biol. 202, 1435-1446.
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