研究生: |
林志信 Chih-Hsin Lin |
---|---|
論文名稱: |
PPP2R2B基因:啟動子記述及Bβ1/Bβ2 isoform在神經退化的角色 PPP2R2B gene: promoter characterization and role of Bβ1/Bβ2 isoform in neurodegeneration |
指導教授: |
李桂楨
Lee, Guey-Jen |
學位類別: |
博士 Doctor |
系所名稱: |
生命科學系 Department of Life Science |
論文出版年: | 2010 |
畢業學年度: | 98 |
語文別: | 英文 |
論文頁數: | 67 |
中文關鍵詞: | 小腦萎縮症第十二型 、PPP2R2B 、啟動子 、CREB1 、SP1 、TFAP4 、細胞週期 、活性氧 、细胞凋亡 、抗氧化劑apoptosis, a |
英文關鍵詞: | spinocerebellar ataxia type 12, PPP2R2B, promoter, CREB1, SP1, TFAP4, cell cycle, reactive oxygen species, apoptosis, antioxidant |
論文種類: | 學術論文 |
相關次數: | 點閱:222 下載:3 |
分享至: |
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PPP2R2B (亦稱為Bβ)廣泛表現在神經元,可調節去磷酸酶PP2A對tau及其他受質的去磷酸化作用。PPP2R2B基因5'端CAG重複擴增,導致體染色體顯性遺傳的神經退化性疾病第十二型小腦萎縮症。相反地,低轉錄活性且稀有短的等位基因,與台灣阿茲海默氏病和原發性顫抖症相關。本論文的第一部分在探討PPP2R2B基因CAG重複序列的角色,和鄰近cis要素及相關蛋白質調控PPP2R2B表現的情形。缺失/特定點突變、電腦模擬、cDNA 過度表現等實驗顯示,CREB1和SP1結合在CAG 重複的上游保守序列,來增加PPP2R2B的表現;然而TFAP4結合在CAG 重複的下游保守序列,來降低PPP2R2B的表現。DNA pull-down和染色質免疫沉澱-聚合酶連鎖反應等實驗進一步證實,CREB1、SP1和TFAP4結合在PPP2R2B起動子上。AT重複置換CAG重複的實驗顯示,CAG重複本身亦為一正調控PPP2R2B表現的cis要素。這些結果顯示CREB1、SP1和TFAP4在調節PPP2R2B表現中扮演角色,因此提供了一個調節PP2A活性的機制。論文的第二部分著重在建立穩定誘導表現Myc標籤的Bβ1/Bβ2細胞株,來探討Bβ調節的PP2A在神經退化中所扮演的角色。被誘導的Bβ1和Bβ2蛋白分別座落在細胞質和粒線體。Bβ細胞株的細胞週期分析顯示Bβ2表現的細胞,subG1和G2/M顯著增加,並伴隨著細胞存活率的顯著降低及cell division cycle (Cdc2)磷酸化的增加。表現Bβ2的細胞其特徵包括:活性氧自由基(ROS)和caspase 3活性增加、粒線體膜電位降低、Bax增加和cytochrome c由粒線體釋出至細胞質等,暗示Bβ2會誘導細胞自戕。抗氧化劑-tocopherol的添加可減弱ROS產生及cytochrome c釋放。總言之,這些結果顯示Bβ2能透過提升粒線體ROS的產生而誘導細胞凋亡。因此抑制Bβ2表現可能被發展為有潛能的治療策略,來治療與PP2A/Bβ2活性增加相關的神經退化性疾病。
PPP2R2B (also known as Bβ), a protein widely expressed in neurons, regulates the protein phosphatase 2A (PP2A) activity for dephosphorylation of tau and other substrates. CAG repeat expansion at the 5' end of the PPP2R2B gene causes autosomal dominant spinocerebellar ataxia type 12. Contrarily, the rare short alleles with low transcriptional activity are associated with Taiwanese Alzheimer's disease and essential tremor. In the first part of the dissertation, the roles of CAG repeats and the flanking cis elements and the associated proteins in controlling PPP2R2B expression were investigated. Deletion/site-directed mutagenesis, in silico searches and cDNA overexpression revealed that CREB1 and SP1 bind to the conserved sequence upstream the CAG repeats to up-regulate PPP2R2B expression, whereas TFAP4 binds to the conserved sequence downstream the CAG repeats to down-regulate PPP2R2B expression. The binding of CREB1, SP1 and TFAP4 to the PPP2R2B promoter was further confirmed by DNA pull-down and ChIP-PCR assays. CAG repeats itself also functions as a cis element to up-regulate PPP2R2B expression as AT repeat length has no effect on PPP2R2B expression. This data provide evidence that CREB1, SP1 and TFAP4 play roles in modulating PPP2R2B expression, thus offering a mechanism of regulating PP2A activity. The second part of the thesis is to uncover the role of Bβ-modulating PP2A in neuronal degeneration using stably induced cell models expressing Myc-tagged Bβ1 and Bβ2. The induced Bβ1 and Bβ2 proteins were mainly localized in cytoplasm and mitochondria, respectively. Cell cycle analysis of Bβ cell lines revealed a significant increase in the cell population at subG1 and G2/M phases in Bβ2-expressing cells, along with significant reduced cell viability and increased inhibitory phosphorylation of cell division cycle 2 (Cdc2). The Bβ2-expressing cells are characterized by increase of reactive oxygen species (ROS) and caspase 3 activity, loss of mitochondrial membrane potential, as well as Bax increase and cytochrome c release, all of which implicate elevated apoptosis. Addition of an antioxidant -tocopherol attenuated ROS production and cytochrome c release. Taken together, these results suggest that Bβ2 is able to induce apoptosis via enhancing mitochondrial ROS production. Thus inhibition of Bβ2 expression may be an attractive avenue for developing potential therapeutic strategies to treat neurodegenerative disorders related to increased PP2A/Bβ2 activity.
侯懿婷 (2005) 退化性神經疾病:PPP2R2B基因族群遺傳分析及分生研究。 國立台灣師範大學生命科學系九十三學年度碩士論文。
Adelman R, Saul RL, Ames BN (1988) Oxidative damage to DNA: relation to species metabolic rate and life span. Proc Natl Acad Sci U S A 85: 2706-8
Aliev G, Obrenovich ME, Reddy VP, Shenk JC, Moreira PI, Nunomura A, Zhu X, Smith MA, Perry G (2008) Antioxidant therapy in Alzheimer's disease: theory and practice. Mini Rev Med Chem 8: 1395-406
Allsop D, Wong CW, Ikeda S, Landon M, Kidd M, Glenner GG (1988) Immunohistochemical evidence for the derivation of a peptide ligand from the amyloid beta-protein precursor of Alzheimer disease. Proc Natl Acad Sci U S A 85: 2790-4
Amici A, Levine RL, Tsai L, Stadtman ER (1989) Conversion of amino acid residues in proteins and amino acid homopolymers to carbonyl derivatives by metal-catalyzed oxidation reactions. J Biol Chem 264: 3341-6
Anborgh PH, Godin C, Pampillo M, Dhami GK, Dale LB, Cregan SP, Truant R, Ferguson SS (2005) Inhibition of metabotropic glutamate receptor signaling by the huntingtin-binding protein optineurin. J Biol Chem 280: 34840-8
Arendt T, Rodel L, Gartner U, Holzer M (1996) Expression of the cyclin-dependent kinase inhibitor p16 in Alzheimer's disease. Neuroreport 7: 3047-9
Ashkenazi A, Dixit VM (1998) Death receptors: signaling and modulation. Science 281: 1305-8
Bartek J, Lukas J (2007) DNA damage checkpoints: from initiation to recovery or adaptation. Curr Opin Cell Biol 19: 238-45
Behl C, Davis J, Cole GM, Schubert D (1992) Vitamin E protects nerve cells from amyloid beta protein toxicity. Biochem Biophys Res Commun 186: 944-50
Bolli R, Jeroudi MO, Patel BS, Aruoma OI, Halliwell B, Lai EK, McCay PB (1989) Marked reduction of free radical generation and contractile dysfunction by antioxidant therapy begun at the time of reperfusion. Evidence that myocardial "stunning" is a manifestation of reperfusion injury. Circ Res 65: 607-22
Bouwman P, Philipsen S (2002) Regulation of the activity of Sp1-related transcription factors. Mol Cell Endocrinol 195: 27-38
Bowser R, Smith MA (2002) Cell cycle proteins in Alzheimer's disease: plenty of wheels but no cycle. J Alzheimers Dis 4: 249-54
Busser J, Geldmacher DS, Herrup K (1998) Ectopic cell cycle proteins predict the sites of neuronal cell death in Alzheimer's disease brain. J Neurosci 18: 2801-7
Butterfield DA, Castegna A, Drake J, Scapagnini G, Calabrese V (2002) Vitamin E and neurodegenerative disorders associated with oxidative stress. Nutr Neurosci 5: 229-39
Byun HO, Kim HY, Lim JJ, Seo YH, Yoon G (2008) Mitochondrial dysfunction by complex II inhibition delays overall cell cycle progression via reactive oxygen species production. J Cell Biochem 104: 1747-59
Chance B, Sies H, Boveris A (1979) Hydroperoxide metabolism in mammalian organs. Physiol Rev 59: 527-605
Chatfield K, Eastman A (2004) Inhibitors of protein phosphatases 1 and 2A differentially prevent intrinsic and extrinsic apoptosis pathways. Biochem Biophys Res Commun 323: 1313-20
Chen CM, Hou YT, Liu JY, Wu YR, Lin CH, Fung HC, Hsu WC, Hsu Y, Lee SH, Hsieh-Li HM, Su MT, Chen ST, Lane HY, Lee-Chen GJ (2009a) PPP2R2B CAG repeat length in the Han Chinese in Taiwan: Association analyses in neurological and psychiatric disorders and potential functional implications. Am J Med Genet B Neuropsychiatr Genet 150B: 124-9
Chen IC, Lin HY, Lee GC, Kao SH, Chen CM, Wu YR, Hsieh-Li HM, Su MT, Lee-Chen GJ (2009b) Spinocerebellar ataxia type 8 larger triplet expansion alters histone modification and induces RNA foci. BMC Mol Biol 10: 9
Cheng WT, Guo ZX, Lin CA, Lin MY, Tung LC, Fang K (2009) Oxidative stress promotes autophagic cell death in human neuroblastoma cells with ectopic transfer of mitochondrial PPP2R2B (Bbeta2). BMC Cell Biol 10: 91
Dagda RK, Barwacz CA, Cribbs JT, Strack S (2005) Unfolding-resistant translocase targeting: a novel mechanism for outer mitochondrial membrane localization exemplified by the Bbeta2 regulatory subunit of protein phosphatase 2A. J Biol Chem 280: 27375-82
Dagda RK, Merrill RA, Cribbs JT, Chen Y, Hell JW, Usachev YM, Strack S (2008) The spinocerebellar ataxia 12 gene product and protein phosphatase 2A regulatory subunit Bbeta2 antagonizes neuronal survival by promoting mitochondrial fission. J Biol Chem 283: 36241-8
Dagda RK, Zaucha JA, Wadzinski BE, Strack S (2003) A developmentally regulated, neuron-specific splice variant of the variable subunit Bbeta targets protein phosphatase 2A to mitochondria and modulates apoptosis. J Biol Chem 278: 24976-85
Dautzenberg FM, Higelin J, Teichert U (2000) Functional characterization of corticotropin-releasing factor type 1 receptor endogenously expressed in human embryonic kidney 293 cells. Eur J Pharmacol 390: 51-9
Davies KJ (1987) Protein damage and degradation by oxygen radicals. I. general aspects. J Biol Chem 262: 9895-901
Davies KJ, Delsignore ME, Lin SW (1987) Protein damage and degradation by oxygen radicals. II. Modification of amino acids. J Biol Chem 262: 9902-7
Deng X, Ito T, Carr B, Mumby M, May WS, Jr. (1998) Reversible phosphorylation of Bcl2 following interleukin 3 or bryostatin 1 is mediated by direct interaction with protein phosphatase 2A. J Biol Chem 273: 34157-63
Dexter DT, Carter CJ, Wells FR, Javoy-Agid F, Agid Y, Lees A, Jenner P, Marsden CD (1989) Basal lipid peroxidation in substantia nigra is increased in Parkinson's disease. J Neurochem 52: 381-9
Ferrigno P, Langan TA, Cohen P (1993) Protein phosphatase 2A1 is the major enzyme in vertebrate cell extracts that dephosphorylates several physiological substrates for cyclin-dependent protein kinases. Mol Biol Cell 4: 669-77
Fleury C, Mignotte B, Vayssiere JL (2002) Mitochondrial reactive oxygen species in cell death signaling. Biochimie 84: 131-41
Forero DA, Casadesus G, Perry G, Arboleda H (2006) Synaptic dysfunction and oxidative stress in Alzheimer's disease: emerging mechanisms. J Cell Mol Med 10: 796-805
Fujigasaki H, Verma IC, Camuzat A, Margolis RL, Zander C, Lebre AS, Jamot L, Saxena R, Anand I, Holmes SE, Ross CA, Durr A, Brice A (2001) SCA12 is a rare locus for autosomal dominant cerebellar ataxia: a study of an Indian family. Ann Neurol 49: 117-21
Gilgun-Sherki Y, Melamed E, Offen D (2001) Oxidative stress induced-neurodegenerative diseases: the need for antioxidants that penetrate the blood brain barrier. Neuropharmacology 40: 959-75
Glatter T, Wepf A, Aebersold R, Gstaiger M (2009) An integrated workflow for charting the human interaction proteome: insights into the PP2A system. Mol Syst Biol 5: 237
Goedert M, Cohen ES, Jakes R, Cohen P (1992a) p42 MAP kinase phosphorylation sites in microtubule-associated protein tau are dephosphorylated by protein phosphatase 2A1. Implications for Alzheimer's disease [corrected]. FEBS Lett 312: 95-9
Goedert M, Spillantini MG, Cairns NJ, Crowther RA (1992b) Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. Neuron 8: 159-68
Gong CX, Grundke-Iqbal I, Iqbal K (1994) Dephosphorylation of Alzheimer's disease abnormally phosphorylated tau by protein phosphatase-2A. Neuroscience 61: 765-72
Gong CX, Shaikh S, Wang JZ, Zaidi T, Grundke-Iqbal I, Iqbal K (1995) Phosphatase activity toward abnormally phosphorylated tau: decrease in Alzheimer disease brain. J Neurochem 65: 732-8
Gong CX, Singh TJ, Grundke-Iqbal I, Iqbal K (1993) Phosphoprotein phosphatase activities in Alzheimer disease brain. J Neurochem 61: 921-7
Gotz J, Chen F, Barmettler R, Nitsch RM (2001) Tau filament formation in transgenic mice expressing P301L tau. J Biol Chem 276: 529-34
Gould KL, Nurse P (1989) Tyrosine phosphorylation of the fission yeast cdc2+ protein kinase regulates entry into mitosis. Nature 342: 39-45
Granger DN (1988) Role of xanthine oxidase and granulocytes in ischemia-reperfusion injury. Am J Physiol 255: H1269-75
Green DR (1998) Apoptosis. Death deceiver. Nature 396: 629-30
Green DR, Reed JC (1998) Mitochondria and apoptosis. Science 281: 1309-12
Halliwell B (1999) Antioxidant defence mechanisms: from the beginning to the end (of the beginning). Free Radic Res 31: 261-72
Halliwell B, Gutteridge JM (1990) Role of free radicals and catalytic metal ions in human disease: an overview. Methods Enzymol 186: 1-85
Handa V, Goldwater D, Stiles D, Cam M, Poy G, Kumari D, Usdin K (2005) Long CGG-repeat tracts are toxic to human cells: implications for carriers of Fragile X premutation alleles. FEBS Lett 579: 2702-8
Harman D (1956) Aging: a theory based on free radical and radiation chemistry. J Gerontol 11: 298-300
Hartwell LH, Weinert TA (1989) Checkpoints: controls that ensure the order of cell cycle events. Science 246: 629-34
Hellenbroich Y, Schulz-Schaeffer W, Nitschke MF, Kohnke J, Handler G, Burk K, Schwinger E, Zuhlke C (2004) Coincidence of a large SCA12 repeat allele with a case of Creutzfeld-Jacob disease. J Neurol Neurosurg Psychiatry 75: 937-8
Hely MA, Fung VS, Morris JG (2000) Treatment of Parkinson's disease. J Clin Neurosci 7: 484-94
Herrup K, Neve R, Ackerman SL, Copani A (2004) Divide and die: cell cycle events as triggers of nerve cell death. J Neurosci 24: 9232-9
Hirai K, Aliev G, Nunomura A, Fujioka H, Russell RL, Atwood CS, Johnson AB, Kress Y, Vinters HV, Tabaton M, Shimohama S, Cash AD, Siedlak SL, Harris PL, Jones PK, Petersen RB, Perry G, Smith MA (2001) Mitochondrial abnormalities in Alzheimer's disease. J Neurosci 21: 3017-23
Holmes SE, O'Hearn E, Margolis RL (2003) Why is SCA12 different from other SCAs? Cytogenet Genome Res 100: 189-97
Holmes SE, O'Hearn EE, McInnis MG, Gorelick-Feldman DA, Kleiderlein JJ, Callahan C, Kwak NG, Ingersoll-Ashworth RG, Sherr M, Sumner AJ, Sharp AH, Ananth U, Seltzer WK, Boss MA, Vieria-Saecker AM, Epplen JT, Riess O, Ross CA, Margolis RL (1999) Expansion of a novel CAG trinucleotide repeat in the 5' region of PPP2R2B is associated with SCA12. Nat Genet 23: 391-2
Hu YF, Luscher B, Admon A, Mermod N, Tjian R (1990) Transcription factor AP-4 contains multiple dimerization domains that regulate dimer specificity. Genes Dev 4: 1741-52
Ito T, Deng X, Carr B, May WS (1997) Bcl-2 phosphorylation required for anti-apoptosis function. J Biol Chem 272: 11671-3
Janssens V, Goris J (2001) Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling. Biochem J 353: 417-39
Janssens V, Goris J, Van Hoof C (2005) PP2A: the expected tumor suppressor. Curr Opin Genet Dev 15: 34-41
Jayalakshmi K, Sairam M, Singh SB, Sharma SK, Ilavazhagan G, Banerjee PK (2005) Neuroprotective effect of N-acetyl cysteine on hypoxia-induced oxidative stress in primary hippocampal culture. Brain Res 1046: 97-104
Jordan-Sciutto KL, Wang G, Murphey-Corb M, Wiley CA (2002) Cell cycle proteins exhibit altered expression patterns in lentiviral-associated encephalitis. J Neurosci 22: 2185-95
Jung-Hynes B, Reiter RJ, Ahmad N Sirtuins, melatonin and circadian rhythms: building a bridge between aging and cancer. J Pineal Res 48: 9-19
Kim MY, Jeong BC, Lee JH, Kee HJ, Kook H, Kim NS, Kim YH, Kim JK, Ahn KY, Kim KK (2006) A repressor complex, AP4 transcription factor and geminin, negatively regulates expression of target genes in nonneuronal cells. Proc Natl Acad Sci U S A 103: 13074-9
Kinoshita M, Yamauchi M, Sasanuma M, Ishikawa Y, Osada T, Inoue K, Wakamatsu Y, Ozato K (2003) A transgene and its expression profile are stably transmitted to offspring in transgenic medaka generated by the particle gun method. Zoolog Sci 20: 869-75
Klebanoff SJ, Waltersdorph AM (1988) Inhibition of peroxidase-catalyzed reactions by deferoxamine. Arch Biochem Biophys 264: 600-6
Kontush A (2001) Amyloid-beta: an antioxidant that becomes a pro-oxidant and critically contributes to Alzheimer's disease. Free Radic Biol Med 31: 1120-31
Lalioti MD, Scott HS, Antonarakis SE (1999) Altered spacing of promoter elements due to the dodecamer repeat expansion contributes to reduced expression of the cystatin B gene in EPM1. Hum Mol Genet 8: 1791-8
Lechward K, Awotunde OS, Swiatek W, Muszynska G (2001) Protein phosphatase 2A: variety of forms and diversity of functions. Acta Biochim Pol 48: 921-33
Lee LC, Chen CM, Chen FL, Lin PY, Hsiao YC, Wang PR, Su MT, Hsieh-Li HM, Hwang JC, Wu CH, Lee GC, Singh S, Lin Y, Hsieh SY, Lee-Chen GJ, Lin JY (2009) Altered expression of HSPA5, HSPA8 and PARK7 in spinocerebellar ataxia type 17 identified by 2-dimensional fluorescence difference in gel electrophoresis. Clin Chim Acta 400: 56-62
Li N, Ragheb K, Lawler G, Sturgis J, Rajwa B, Melendez JA, Robinson JP (2003) Mitochondrial complex I inhibitor rotenone induces apoptosis through enhancing mitochondrial reactive oxygen species production. J Biol Chem 278: 8516-25
Libby RT, Hagerman KA, Pineda VV, Lau R, Cho DH, Baccam SL, Axford MM, Cleary JD, Moore JM, Sopher BL, Tapscott SJ, Filippova GN, Pearson CE, La Spada AR (2008) CTCF cis-regulates trinucleotide repeat instability in an epigenetic manner: a novel basis for mutational hot spot determination. PLoS Genet 4: e1000257
Love S (2003) Neuronal expression of cell cycle-related proteins after brain ischaemia in man. Neurosci Lett 353: 29-32
Lu C, Ren W, Su XM, Chen JQ, Wu SH, Guo XR, Huang SM, Chen LH, Zhou GP (2008) CREB and Sp1 regulate the human CD2AP gene promoter activity in renal tubular epithelial cells. Arch Biochem Biophys 474: 143-9
Ma J, Wollmann R, Lindquist S (2002) Neurotoxicity and neurodegeneration when PrP accumulates in the cytosol. Science 298: 1781-5
Mattson MP, Gleichmann M, Cheng A (2008) Mitochondria in neuroplasticity and neurological disorders. Neuron 60: 748-66
May WS, Tyler PG, Ito T, Armstrong DK, Qatsha KA, Davidson NE (1994) Interleukin-3 and bryostatin-1 mediate hyperphosphorylation of BCL2 alpha in association with suppression of apoptosis. J Biol Chem 269: 26865-70
Mayer RE, Hendrix P, Cron P, Matthies R, Stone SR, Goris J, Merlevede W, Hofsteenge J, Hemmings BA (1991) Structure of the 55-kDa regulatory subunit of protein phosphatase 2A: evidence for a neuronal-specific isoform. Biochemistry 30: 3589-97
Millward TA, Zolnierowicz S, Hemmings BA (1999) Regulation of protein kinase cascades by protein phosphatase 2A. Trends Biochem Sci 24: 186-91
Montminy MR, Sevarino KA, Wagner JA, Mandel G, Goodman RH (1986) Identification of a cyclic-AMP-responsive element within the rat somatostatin gene. Proc Natl Acad Sci U S A 83: 6682-6
Morris MC, Evans DA, Bienias JL, Tangney CC, Bennett DA, Aggarwal N, Wilson RS, Scherr PA (2002) Dietary intake of antioxidant nutrients and the risk of incident Alzheimer disease in a biracial community study. JAMA 287: 3230-7
Muller FL, Liu Y, Van Remmen H (2004) Complex III releases superoxide to both sides of the inner mitochondrial membrane. J Biol Chem 279: 49064-73
Okouchi M, Ekshyyan O, Maracine M, Aw TY (2007) Neuronal apoptosis in neurodegeneration. Antioxid Redox Signal 9: 1059-96
Oliver CN, Ahn BW, Moerman EJ, Goldstein S, Stadtman ER (1987) Age-related changes in oxidized proteins. J Biol Chem 262: 5488-91
Piera-Velazquez S, Hawkins DF, Whitecavage MK, Colter DC, Stokes DG, Jimenez SA (2007) Regulation of the human SOX9 promoter by Sp1 and CREB. Exp Cell Res 313: 1069-79
Quinn PG (1993) Distinct activation domains within cAMP response element-binding protein (CREB) mediate basal and cAMP-stimulated transcription. J Biol Chem 268: 16999-7009
Raca G, Siyanova EY, McMurray CT, Mirkin SM (2000) Expansion of the (CTG)(n) repeat in the 5'-UTR of a reporter gene impedes translation. Nucleic Acids Res 28: 3943-9
Ranganathan S, Bowser R (2003) Alterations in G(1) to S phase cell-cycle regulators during amyotrophic lateral sclerosis. Am J Pathol 162: 823-35
Ruvolo PP, Deng X, Carr BK, May WS (1998) A functional role for mitochondrial protein kinase Calpha in Bcl2 phosphorylation and suppression of apoptosis. J Biol Chem 273: 25436-42
Ruvolo PP, Deng X, Ito T, Carr BK, May WS (1999) Ceramide induces Bcl2 dephosphorylation via a mechanism involving mitochondrial PP2A. J Biol Chem 274: 20296-300
Salganik RI (2001) The benefits and hazards of antioxidants: controlling apoptosis and other protective mechanisms in cancer patients and the human population. J Am Coll Nutr 20: 464S-472S; discussion 473S-475S
Sano M, Ernesto C, Thomas RG, Klauber MR, Schafer K, Grundman M, Woodbury P, Growdon J, Cotman CW, Pfeiffer E, Schneider LS, Thal LJ (1997) A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study. N Engl J Med 336: 1216-22
Santoro MF, Annand RR, Robertson MM, Peng YW, Brady MJ, Mankovich JA, Hackett MC, Ghayur T, Walter G, Wong WW, Giegel DA (1998) Regulation of protein phosphatase 2A activity by caspase-3 during apoptosis. J Biol Chem 273: 13119-28
Sassone-Corsi P (1995) Transcription factors responsive to cAMP. Annu Rev Cell Dev Biol 11: 355-77
Satoh J, Yamamura T (2004) Gene expression profile following stable expression of the cellular prion protein. Cell Mol Neurobiol 24: 793-814
Sawyer DB, Siwik DA, Xiao L, Pimentel DR, Singh K, Colucci WS (2002) Role of oxidative stress in myocardial hypertrophy and failure. J Mol Cell Cardiol 34: 379-88
Shaw G, Morse S, Ararat M, Graham FL (2002) Preferential transformation of human neuronal cells by human adenoviruses and the origin of HEK 293 cells. FASEB J 16: 869-71
Shigenaga MK, Gimeno CJ, Ames BN (1989) Urinary 8-hydroxy-2'-deoxyguanosine as a biological marker of in vivo oxidative DNA damage. Proc Natl Acad Sci U S A 86: 9697-701
Sontag E, Nunbhakdi-Craig V, Lee G, Bloom GS, Mumby MC (1996) Regulation of the phosphorylation state and microtubule-binding activity of Tau by protein phosphatase 2A. Neuron 17: 1201-7
Sontag E, Nunbhakdi-Craig V, Lee G, Brandt R, Kamibayashi C, Kuret J, White CL, 3rd, Mumby MC, Bloom GS (1999) Molecular interactions among protein phosphatase 2A, tau, and microtubules. Implications for the regulation of tau phosphorylation and the development of tauopathies. J Biol Chem 274: 25490-8
St-Pierre J, Buckingham JA, Roebuck SJ, Brand MD (2002) Topology of superoxide production from different sites in the mitochondrial electron transport chain. J Biol Chem 277: 44784-90
Stadtman ER (1986) Oxidation of proteins by mixed-function oxidation systems: implication in protein turnover, ageing and neutrophil function. Trends Biochem Sci 11: 11-12
Strack S, Zaucha JA, Ebner FF, Colbran RJ, Wadzinski BE (1998) Brain protein phosphatase 2A: developmental regulation and distinct cellular and subcellular localization by B subunits. J Comp Neurol 392: 515-27
Teive HA (2009) Spinocerebellar ataxias. Arq Neuropsiquiatr 67: 1133-42
Turowski P, Myles T, Hemmings BA, Fernandez A, Lamb NJ (1999) Vimentin dephosphorylation by protein phosphatase 2A is modulated by the targeting subunit B55. Mol Biol Cell 10: 1997-2015
Vermeulen K, Van Bockstaele DR, Berneman ZN (2003) The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer. Cell Prolif 36: 131-49
Vincent I, Rosado M, Davies P (1996) Mitotic mechanisms in Alzheimer's disease? J Cell Biol 132: 413-25
Virshup DM (2000) Protein phosphatase 2A: a panoply of enzymes. Curr Opin Cell Biol 12: 180-5
Wang YH, Amirhaeri S, Kang S, Wells RD, Griffith JD (1994) Preferential nucleosome assembly at DNA triplet repeats from the myotonic dystrophy gene. Science 265: 669-71
Weitzman SA, Gordon LI (1990) Inflammation and cancer: role of phagocyte-generated oxidants in carcinogenesis. Blood 76: 655-63
Wood JG, Mirra SS, Pollock NJ, Binder LI (1986) Neurofibrillary tangles of Alzheimer disease share antigenic determinants with the axonal microtubule-associated protein tau (tau). Proc Natl Acad Sci U S A 83: 4040-3
Zandi PP, Anthony JC, Khachaturian AS, Stone SV, Gustafson D, Tschanz JT, Norton MC, Welsh-Bohmer KA, Breitner JC (2004) Reduced risk of Alzheimer disease in users of antioxidant vitamin supplements: the Cache County Study. Arch Neurol 61: 82-8
Zhu X, Rottkamp CA, Boux H, Takeda A, Perry G, Smith MA (2000) Activation of p38 kinase links tau phosphorylation, oxidative stress, and cell cycle-related events in Alzheimer disease. J Neuropathol Exp Neurol 59: 880-8