1. NCCU Academic Hub
  2. 學術產出
  3. 理學院
  4. 學位論文
  5. Item

學術產出-學位論文

文章檢視/開啟

書目匯出

Google ScholarTM

政大圖書館

引文資訊

TAIR相關學術產出

題名 蛋白激酶 CK2 調控受質蛋白 DARPP-32 磷酸化對 PC12 細胞株之抗凋亡機制的探討
DARPP-32 phosphorylation by protein kinase CK2 mediates the anti-apoptotic effects in PC12 cells
作者 李曉怡
Lee, Hsiao Yi
貢獻者 趙知章
李曉怡
Lee, Hsiao Yi
關鍵詞 蛋白激酶CK2
DARPP-32蛋白
抗細胞凋亡Bcl-xL蛋白
促細胞凋亡Bcl-xS蛋白
抗細胞凋亡
protein kinase CK2
DARPP-32
Bcl-xL
Bcl-xS
anti-apoptosis
日期 2010
上傳時間 12-四月-2012 14:12:31 (UTC+8)
摘要 蛋白激酶 CK2 是一種具有多種功能的絲胺酸/蘇胺酸蛋白質激酶，其作用的受質眾多且普遍存在於哺乳類動物細胞中。從許多的研究結果顯示，蛋白激酶 CK2 參與調節許多的神經系統功能其中包括有神經保護作用，但是其分子層面的機制目前尚未釐清。DARPP-32（Dopamine- and cAMP-regulated phosphoprotein, Mr 32 kDa）主要表現在紋狀體中型多刺狀 GABA 神經元中的蛋白質，參與調控與藥物成癮相關的多巴胺訊息傳遞路徑，不過，近年來的一些研究報告指出DARPP-32亦參與了細胞的抗凋亡作用。雖然先前已有研究發現DARPP-32 Ser102胺基酸是CK2的磷酸化作用受質，但是並沒有進一步的研究證實，該胺基酸的磷酸化作用是否參與CK2所調控的細胞機制。屬於抗細胞凋亡蛋白Bcl-2 家族成員之ㄧ的bcl-x基因會經由pre-mRNA選擇性剪裁機制（alternative splicing）而產生兩種異構蛋白Bcl-xL和Bcl-xS，其中Bcl-xL蛋白被證實會促進細胞存活；而Bcl-xS蛋白則會造成細胞死亡。實驗室先前的研究結果發現，在神經滋養因子BDNF的刺激下，CK2可以促進Bcl-xL基因的表現，因此本論文欲進一步探討CK2對DARPP-32 Ser102的磷酸化作用是否參與CK2的抗細胞凋亡訊息傳遞，進而影響Bcl-xL和Bcl-xS的表現。實驗結果顯示，轉染野生型CK2α DNA質體會增加DARPP-32 Ser102的磷酸化現象、Bcl-xL的蛋白質表現以及Bcl-xL/Bcl-xS mRNA的比例；而處理 CK2 抑制劑 TBB 或轉染 CK2α siRNA則會降低 DARPP-32 Ser102的磷酸化現象、Bcl-xL的蛋白質表現以及Bcl-xL/Bcl-xS mRNA的比例。此外，轉染 DARPP-32 siRNA會降低 Bcl-xL的蛋白質表現。轉染模擬之磷酸化構型的DARPP-32 S102D DNA質體會增加Bcl-xL的蛋白質表現以及Bcl-xL/Bcl-xS mRNA的比例；但是，轉染突變型DARPP-32 S102A DNA質體則會降低Bcl-xL的蛋白質表現以及Bcl-xL/Bcl-xS mRNA的比例。進一步利用野生型CK2α和DARPP-32 S102A DNA質體進行細胞共同轉染的實驗結果則發現，DARPP-32 S102A會拮抗野生型 CK2α對促進Bcl-xL蛋白質表現的作用；另外，利用過氧過氫產生細胞氧化逆境下，CK2α或DARPP-32 siRNA處理可以顯著降低 DARPP-32 Ser102的磷酸化現象、Bcl-xL的蛋白質表現以及Bcl-xL/Bcl-xS mRNA的比例，同時會顯著造成細胞凋亡。綜合本論文的實驗結果，顯示CK2會透過DARPP-32 Ser102的磷酸化作用而調控Bcl-xL以及Bcl-xS的表現，而且在氧化逆境下，此條細胞訊息傳遞路徑應參與了細胞的抗凋亡機制。
Protein kinase CK2 is a multifunctional serine/threonine protein kinase with many protein substrares and is ubiquitously expressed in mammalian cells. Many studies have shown that CK2 is involved in many neuronal functions including neuroprotection, but its cellular mechanisms are not well-studied. DARPP-32 (Dopamine- and cAMP-regulated phosphoprotein, Mr 32 kDa) is highly enriched in striatal medium-size spiny GABA neurons and is a prominent mediator of dopamine signalling which relates with drug abuse. Beside its well-known function in drug abuse, recent studies also reveal that DARPP-32 may be involved in the anti-apoptotic effects. Although the Ser102 residue of DARPP-32 is a phosphorylation site for CK2, this phosphorylation-mediated CK2 signaling has not been studied yet. The bcl-x gene, one member of the Bcl-2 family, encodes two isoform proteins Bcl-xL and Bcl-xS by the pre-mRNA alternative splicing. The former increases cell survival and the later enhances cell apoptosis. Our previous study found that CK2 can increase Bcl-xL expression by BDNF treatment. In the present study, we investigate whether DARPP-32 ser102 phosphorylation also mediates the CK2 signaling for cell survival. Our results revealed that DARPP-32 Ser102 phosphorylation, Bcl-xL protein level and Bcl-xL/Bcl-xS mRNA ratio were all increased by wild-type CK2α plasmid DNA transfection. Meanwhile, CK2 inhibitor TBB treatment or CK2α siRNA transfection decreased DARPP-32 Ser102 phosphorylation, Bcl-xL protein level and Bcl-xL/Bcl-xS mRNA ratio. On the other hand, DARPP-32 siRNA transfection decreased Bcl-xL protein level. Furthermore, transfection of DARPP-32 S102D, which mimics the constitutive phosphorylation form, increased whereas transfection of mutant S102A decreased the Bcl-xL protein level and Bcl-xL/Bcl-xS mRNA ratio. Further, the mutant DARPP-32 S102A antagonized the up-regulatory effects of wild-type CK2α on Bcl-xL protein level in the co-transfection experiments. From the results of H2O2-induced oxidative stress experiments, we also found that prior knock-down of CK2 or DARPP-32 can aggravate the decrease in DARPP-32 Ser102 phosphorylation, Bcl-xL protein level and Bcl-xL/Bcl-xS mRNA ratio by H2O2 treatment. These results together suggest that DARPP-32 mediates CK2α signaling in regulating Bcl-xL/Bcl-xS expression and this signaling pathway might be involved in cell survival under oxidative stress.
參考文獻 Ahn JH, McAvoy T, Rakhilin SV, Nishi A, Greengard P, Nairn AC (2007) Protein kinase A activates protein phosphatase 2A by phosphorylation of the B56delta subunit. Proc Natl Acad Sci U S A 104:2979-2984.
Aksenova MV, Burbaeva GS, Kandror KV, Kapkov DV, Stepanov AS (1991) The decreased level of casein kinase 2 in brain cortex of schizophrenic and Alzheimer`s disease patients. FEBS Lett 279:55-57.
Apostol BL, Illes K, Pallos J, Bodai L, Wu J, Strand A, Schweitzer ES, Olson JM, Kazantsev A, Marsh JL, Thompson LM (2006) Mutant huntingtin alters MAPK signaling pathways in PC12 and striatal cells: ERK1/2 protects against mutant huntingtin-associated toxicity. Hum Mol Genet 15:273-285.
Bateup HS, Santini E, Shen W, Birnbaum S, Valjent E, Surmeier DJ, Fisone G, Nestler EJ, Greengard P (2010) Distinct subclasses of medium spiny neurons differentially regulate striatal motor behaviors. Proc Natl Acad Sci U S A 107:14845-14850.
Bateup HS, Svenningsson P, Kuroiwa M, Gong S, Nishi A, Heintz N, Greengard P (2008) Cell type-specific regulation of DARPP-32 phosphorylation by psychostimulant and antipsychotic drugs. Nat Neurosci 11:932-939.
Belkhiri A, Zaika A, Pidkovka N, Knuutila S, Moskaluk C, El-Rifai W (2005) Darpp-32: a novel antiapoptotic gene in upper gastrointestinal carcinomas. Cancer Res 65:6583-6592.
Bibb JA, Snyder GL, Nishi A, Yan Z, Meijer L, Fienberg AA, Tsai LH, Kwon YT, Girault JA, Czernik AJ, Huganir RL, Hemmings HC, Jr., Nairn AC, Greengard P (1999) Phosphorylation of DARPP-32 by Cdk5 modulates dopamine signalling in neurons. Nature 402:669-671.
Bibb JA, Yan Z, Svenningsson P, Snyder GL, Pieribone VA, Horiuchi A, Nairn AC, Messer A, Greengard P (2000) Severe deficiencies in dopamine signaling in presymptomatic Huntington`s disease mice. Proc Natl Acad Sci U S A 97:6809-6814.
Blanquet PR (1998) Neurotrophin-induced activation of casein kinase 2 in rat hippocampal slices. Neuroscience 86:739-749.
Boise LH, Gonzalez-Garcia M, Postema CE, Ding L, Lindsten T, Turka LA, Mao X, Nunez G, Thompson CB (1993) bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell 74:597-608.
Bonoiu AC, Mahajan SD, Ding H, Roy I, Yong KT, Kumar R, Hu R, Bergey EJ, Schwartz SA, Prasad PN (2009) Nanotechnology approach for drug addiction therapy: gene silencing using delivery of gold nanorod-siRNA nanoplex in dopaminergic neurons. Proc Natl Acad Sci U S A 106:5546-5550.
Boon-Unge K, Yu Q, Zou T, Zhou A, Govitrapong P, Zhou J (2007) Emetine Regulates the Alternative Splicing of Bcl-x through a Protein Phosphatase 1-Dependent Mechanism. Chem Biol 14:1386-1392.
Bredesen DE, Rao RV, Mehlen P (2006) Cell death in the nervous system. Nature 443:796-802.
Buchou T, Vernet M, Blond O, Jensen HH, Pointu H, Olsen BB, Cochet C, Issinger OG, Boldyreff B (2003) Disruption of the regulatory beta subunit of protein kinase CK2 in mice leads to a cell-autonomous defect and early embryonic lethality. Mol Cell Biol 23:908-915.
Burnett G, Kennedy EP (1954) The enzymatic phosphorylation of proteins. J Biol Chem 211:969-980.
Cash R, Raisman R, Ploska A, Agid Y (1987) Dopamine D-1 receptor and cyclic AMP-dependent phosphorylation in Parkinson`s disease. J Neurochem 49:1075-1083.
Chalfant CE, Rathman K, Pinkerman RL, Wood RE, Obeid LM, Ogretmen B, Hannun YA (2002) De novo ceramide regulates the alternative splicing of caspase 9 and Bcl-x in A549 lung adenocarcinoma cells. Dependence on protein phosphatase-1. J Biol Chem 277:12587-12595.
Chao CC, Chiang CH, Ma YL, Lee EH (2006) Molecular mechanism of the neurotrophic effect of GDNF on DA neurons: role of protein kinase CK2. Neurobiol Aging 27:105-118.
Chao CC, Ma YL, Lee EH (2011) Brain-derived neurotrophic factor enhances Bcl-xL expression through protein kinase casein kinase 2-activated and nuclear factor kappa B-mediated pathway in rat hippocampus. Brain Pathol 21:150-162.
Charriaut-Marlangue C, Otani S, Creuzet C, Ben-Ari Y, Loeb J (1991) Rapid activation of hippocampal casein kinase II during long-term potentiation. Proc Natl Acad Sci U S A 88:10232-10236.
Chester N, Yu IJ, Marshak DR (1995) Identification and characterization of protein kinase CKII isoforms in HeLa cells. Isoform-specific differences in rates of assembly from catalytic and regulatory subunits. J Biol Chem 270:7501-7514.
Cho ES, Lee KW, Lee HJ (2008) Cocoa procyanidins protect PC12 cells from hydrogen-peroxide-induced apoptosis by inhibiting activation of p38 MAPK and JNK. Mutat Res 640:123-130.
Deigner HP, Haberkorn U, Kinscherf R (2000) Apoptosis modulators in the therapy of neurodegenerative diseases. Expert Opin Investig Drugs 9:747-764.
Desagher S, Osen-Sand A, Montessuit S, Magnenat E, Vilbois F, Hochmann A, Journot L, Antonsson B, Martinou JC (2001) Phosphorylation of bid by casein kinases I and II regulates its cleavage by caspase 8. Mol Cell 8:601-611.
Desdouits F, Siciliano JC, Nairn AC, Greengard P, Girault JA (1998) Dephosphorylation of Ser-137 in DARPP-32 by protein phosphatases 2A and 2C: different roles in vitro and in striatonigral neurons. Biochem J 330 211-216.
Di Maira G, Salvi M, Arrigoni G, Marin O, Sarno S, Brustolon F, Pinna LA, Ruzzene M (2005) Protein kinase CK2 phosphorylates and upregulates Akt/PKB. Cell Death Differ 12:668-677.
Diaz-Nido J, Serrano L, Mendez E, Avila J (1988) A casein kinase II-related activity is involved in phosphorylation of microtubule-associated protein MAP-1B during neuroblastoma cell differentiation. J Cell Biol 106:2057-2065.
Doeppner TR, El Aanbouri M, Dietz GP, Weise J, Schwarting S, Bahr M (2010) Transplantation of TAT-Bcl-xL-transduced neural precursor cells: long-term neuroprotection after stroke. Neurobiol Dis 40:265-276.
Dole MG, Clarke MF, Holman P, Benedict M, Lu J, Jasty R, Eipers P, Thompson CB, Rode C, Bloch C, Nunez, Castle VP (1996) Bcl-xS enhances adenoviral vector-induced apoptosis in neuroblastoma cells. Cancer Res 56:5734-5740.
El-Rifai W, Smith MF, Jr., Li G, Beckler A, Carl VS, Montgomery E, Knuutila S, Moskaluk CA, Frierson HF, Jr., Powell SM (2002) Gastric cancers overexpress DARPP-32 and a novel isoform, t-DARPP. Cancer Res 62:4061-4064.
Fienberg AA, Greengard P (2000) The DARPP-32 knockout mouse. Brain Res Brain Res Rev 31:313-319.
Fienberg AA, Hiroi N, Mermelstein PG, Song W, Snyder GL, Nishi A, Cheramy A, O`Callaghan JP, Miller DB, Cole DG, Corbett R, Haile CN, Cooper DC, Onn SP, Grace AA, Ouimet CC, White FJ, Hyman SE, Surmeier DJ, Girault J, Nestler EJ, Greengard P (1998) DARPP-32: Regulator of the Efficacy of Dopaminergic Neurotransmission. Science 281:838-842.
Garcia-Jimenez C, Zaballos MA, Santisteban P (2005) DARPP-32 (Dopamine and 3`,5`-Cyclic Adenosine Monophosphate-Regulated Neuronal Phosphoprotein) Is Essential for the Maintenance of Thyroid Differentiation. Mol Endocrinol 19:3060-3072.
Gerfen CR, Engber TM, Mahan LC, Susel Z, Chase TN, Monsma FJ, Jr., Sibley DR (1990) D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons. Science 250:1429-1432.
Girault JA, Hemmings HC, Jr, Williams KR, Nairn AC, Greengard P (1989) Phosphorylation of DARPP-32, a dopamine- and cAMP-regulated phosphoprotein, by casein kinase II. J Biol Chem 264:21748--21759.
Girault JA, Hemmings HC, Jr., Zorn SH, Gustafson EL, Greengard P (1990) Characterization in mammalian brain of a DARPP-32 serine kinase identical to casein kinase II. J Neurochem 55:1772-1783.
Goldstein JC, Waterhouse NJ, Juin P, Evan GI, Green DR (2000) The coordinate release of cytochrome c during apoptosis is rapid, complete and kinetically invariant. Nat Cell Biol 2:156-162.
Gorman AM, McGowan A, O`Neill C, Cotter T (1996) Oxidative stress and apoptosis in neurodegeneration. J Neurol Sci 139 Suppl:45-52.
Green DR (2005) Apoptotic pathways: ten minutes to dead. Cell 121:671-674.
Green DR, Reed JC (1998) Mitochondria and apoptosis. Science 281:1309-1312.
Greene LA, Tischler AS (1976) Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Proc Natl Acad Sci U S A 73:2424-2428.
Greengard P (2001) The Neurobiology of Slow Synaptic Transmission. Science 294:1024-1030.
Greengard P, Allen PB, Nairn AC (1999) Beyond the dopamine receptor: the DARPP-32/protein phosphatase-1 cascade. Neuron 23:435-447.
Hakansson K, Galdi S, Hendrick J, Snyder G, Greengard P, Fisone G (2006) Regulation of phosphorylation of the GluR1 AMPA receptor by dopamine D2 receptors. J Neurochem 96:482-488.
Hamada M, Hendrick JP, Ryan GR, Kuroiwa M, Higashi H, Tanaka M, Nairn AC, Greengard P, Nishi A (2005) Nicotine Regulates DARPP-32 (Dopamine- and cAMP-Regulated Phosphoprotein of 32 kDa) Phosphorylation at Multiple Sites in Neostriatal Neurons. J Pharmacol Exp Ther 315:872-878.
Hemmings HC, Jr., Nairn AC, Elliott JI, Greengard P (1990) Synthetic peptide analogs of DARPP-32 (Mr 32,000 dopamine- and cAMP-regulated phosphoprotein), an inhibitor of protein phosphatase-1. Phosphorylation, dephosphorylation, and inhibitory activity. J Biol Chem 265:20369-20376.
Homma MK, Wada I, Suzuki T, Yamaki J, Krebs EG, Homma Y (2005) CK2 phosphorylation of eukaryotic translation initiation factor 5 potentiates cell cycle progression. Proc Natl Acad Sci U S A 102:15688-15693.
Izeradjene K, Douglas L, Delaney A, Houghton JA (2005) Casein kinase II (CK2) enhances death-inducing signaling complex (DISC) activity in TRAIL-induced apoptosis in human colon carcinoma cell lines. Oncogene 24:2050-2058.
Jang JH, Surh YJ (2001) Protective effects of resveratrol on hydrogen peroxide-induced apoptosis in rat pheochromocytoma (PC12) cells. Mutat Res 496:181-190.
Kim HJ, Lee KW, Kim MS, Lee HJ (2008a) Piceatannol attenuates hydrogen-peroxide- and peroxynitrite-induced apoptosis of PC12 cells by blocking down-regulation of Bcl-XL and activation of JNK. J Nutr Biochem 19:459-466.
Kim HR, Kim K, Lee KH, Kim SJ, Kim J (2008b) Inhibition of casein kinase 2 enhances the death ligand- and natural kiler cell-induced hepatocellular carcinoma cell death. Clin Exp Immunol 152:336-344.
Kluck RM, Bossy-Wetzel E, Green DR, Newmeyer DD (1997) The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis. Science 275:1132-1136.
Kuwana T, Bouchier-Hayes L, Chipuk JE, Bonzon C, Sullivan BA, Green DR, Newmeyer DD (2005) BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly. Mol Cell 17:525-535.
Laramas M, Pasquier D, Filhol O, Ringeisen F, Descotes JL, Cochet C (2007) Nuclear localization of protein kinase CK2 catalytic subunit (CK2alpha) is associated with poor prognostic factors in human prostate cancer. Eur J Cancer 43:928-934.
Letai A, Bassik MC, Walensky LD, Sorcinelli MD, Weiler S, Korsmeyer SJ (2002) Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell 2:183-192.
Liu FC, Graybiel AM (1996) Spatiotemporal dynamics of CREB phosphorylation: transient versus sustained phosphorylation in the developing striatum. Neuron 17:1133-1144.
Liu R, Page C, Beidler DR, Wicha MS, Nunez G (1999) Overexpression of Bcl-x(L) promotes chemotherapy resistance of mammary tumors in a syngeneic mouse model. Am J Pathol 155:1861-1867.
Lou DY, Dominguez I, Toselli P, Landesman-Bollag E, O`Brien C, Seldin DC (2008) The alpha catalytic subunit of protein kinase CK2 is required for mouse embryonic development. Mol Cell Biol 28:131-139.
Mahajan SD, Aalinkeel R, Reynolds JL, Nair BB, Sykes DE, Hu Z, Bonoiu A, Ding H, Prasad PN, Schwartz SA (2009a) Therapeutic targeting of "DARPP-32": a key signaling molecule in the dopiminergic pathway for the treatment of opiate addiction. Int Rev Neurobiol 88:199-222.
Mahajan SD, Aalinkeel R, Reynolds JL, Nair BB, Sykes DE, Hu Z, Bonoiu A, Ding H, Prasad PN, Schwartz SA (2009b) Therapeutic Targeting of “DARPP-32”A Key Signaling Molecule in the Dopiminergic Pathway for the Treatment of Opiate Addiction. Int Rev Neurobiol 88:199-222.
Matsura T, Kai M, Fujii Y, Ito H, Yamada K (1999) Hydrogen peroxide-induced apoptosis in HL-60 cells requires caspase-3 activation. Free Radic Res 30:73-83.
McKendrick L, Milne D, Meek D (1999) Protein kinase CK2-dependent regulation of p53 function: evidence that the phosphorylation status of the serine 386 (CK2) site of p53 is constitutive and stable. Mol Cell Biochem 191:187-199.
Meggio F, Pinna LA (2003) One-thousand-and-one substrates of protein kinase CK2? FASEB J 17:349-368.
Murnion ME, Adams RR, Callister DM, Allis CD, Earnshaw WC, Swedlow JR (2001) Chromatin-associated Protein Phosphatase 1 Regulates Aurora-B and Histone H3 Phosphorylation. J Biol Chem 276:26656-26665.
Nishi A, Bibb JA, Snyder GL, Higashi H, Nairn AC, Greengard P (2000) Amplification of dopaminergic signaling by a positive feedback loop. Proc Natl Acad Sci U S A 97:12840-12845.
Nishi A, Snyder GL, Nairn AC, Greengard P (1999) Role of calcineurin and protein phosphatase-2A in the regulation of DARPP-32 dephosphorylation in neostriatal neurons. J Neurochem 72:2015-2021.
Ouimet CC, Miller PE, Hemmings HC, Walaas SI, Greengard P (1984) DARPP-32, a dopamine- and adenosine 3`:5`-monophosphate-regulated phosphoprotein enriched in dopamine-innervated brain regions. III. Immunocytochemical localization. J Neurosci 4:111-124.
Salvesen GS, Dixit VM (1997) Caspases: intracellular signaling by proteolysis. Cell 91:443-446.
Sarno S, Reddy H, Meggio F, Ruzzene M, Davies SP, Donella-Deana A, Shugar D, Pinna LA (2001) Selectivity of 4,5,6,7-tetrabromobenzotriazole, an ATP site-directed inhibitor of protein kinase CK2 ("casein kinase-2`). FEBS Lett 496:44-48.
Schneider CC, Hessenauer A, Gotz C, Montenarh M (2009) DMAT, an inhibitor of protein kinase CK2 induces reactive oxygen species and DNA double strand breaks. Oncol Rep 21:1593-1597.
Sekharam M, Zhao H, Sun M, Fang Q, Zhang Q, Yuan Z, Dan HC, Boulware D, Cheng JQ, Coppola D (2003) Insulin-like growth factor 1 receptor enhances invasion and induces resistance to apoptosis of colon cancer cells through the Akt/Bcl-x(L) pathway. Cancer Res 63:7708-7716.
Stipanovich A, Valjent E, Matamales M, Nishi A, Ahn JH, Maroteaux M, Bertran-Gonzalez J, Brami-Cherrier K, Enslen H, Corbillé AG, Filhol O, Nairn AC, Greengard P, Hervé D, Girault JA (2008) A phosphatase cascade by which rewarding stimuli control nucleosomal response. Nature 453:879-884.
Stoof JC, Kebabian JW (1981) Opposing roles for D-1 and D-2 dopamine receptors in efflux of cyclic AMP from rat neostriatum. Nature 294:366-368.
Stumm G, Schlegel J, Schafer T, Wurz C, Mennel HD, Krieg JC, Vedder H (1999) Amphetamines induce apoptosis and regulation of bcl-x splice variants in neocortical neurons. FASEB J 13:1065-1072.
Svenningsson P, Nishi A, Fisone G, Girault J-A, Nairn AC, Greengard P (2004) DARPP-32: An Integrator of Neurotransmission. Annu Rev Pharmacol Toxicol 44:269-296.
Ulery PG, Rudenko G, Nestler EJ (2006) Regulation of FosB Stability by Phosphorylation. J Neurosci 26:5131-5142.
Valjent E, Pascoli V, Svenningsson P, Paul S, Enslen H, Corvol JC, Stipanovich A, Caboche J, Lombroso PJ, Nairn AC, Greengard P, Hervé D, Girault JA (2005) Regulation of a protein phosphatase cascade allows convergent dopamine and glutamate signals to activate ERK in the striatum. Proceedings of the National Academy of Sciences 102:491-496.
Walaas SI, Aswad DW, Greengard P (1983) A dopamine- and cyclic AMP-regulated phosphoprotein enriched in dopamine-innervated brain regions. Nature 301:69–71.
Walaas SI, Greengard p (1984) DARPP-32, a dopamine- and adenosine 3`:5`-monophosphate-regulated phosphoprotein enriched in dopamine-innervated brain regions. I. Regional and cellular distribution in the rat brain. J Neurosci 4:84-98.
Wei MC, Lindsten T, Mootha VK, Weiler S, Gross A, Ashiya M, Thompson CB, Korsmeyer SJ (2000) tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c. Genes Dev 14:2060-2071.
Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, Ross AJ, Roth KA, MacGregor GR, Thompson CB, Korsmeyer SJ (2001) Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292:727-730.
Yang H, Sadda MR, Li M, Zeng Y, Chen L, Bae W, Ou X, Runnegar MT, Mato JM, Lu SC (2004) S-adenosylmethionine and its metabolite induce apoptosis in HepG2 cells: Role of protein phosphatase 1 and Bcl-x(S). Hepatology 40:221-231.
Zachariou V, Sgambato-Faure V, Sasaki T, Svenningsson P, Berton O, Fienberg AA, Nairn AC, Greengard P, Nestler EJ (2006) Phosphorylation of DARPP-32 at Threonine-34 is required for cocaine action. Neuropsychopharmacology 31:555-562.
Zhang Y, Svenningsson P, Picetti R, Schlussman SD, Nairn AC, Ho A, Greengard P, Kreek MJ (2006) Cocaine self-administration in mice is inversely related to phosphorylation at Thr34 (protein kinase A site) and Ser130 (kinase CK1 site) of DARPP-32. J Neurosci 26:2645-2651.
Zhu S, Belkhiri A, El-Rifai W (2011) DARPP-32 Increases Interactions Between Epidermal Growth Factor Receptor and ERBB3 to Promote Tumor Resistance to Gefitinib. Gastroenterology.
描述 碩士
國立政治大學
神經科學研究所
98754005
99
資料來源 http://thesis.lib.nccu.edu.tw/record/#G0098754005
資料類型 thesis
dc.contributor.advisor 趙知章zh_TW
dc.contributor.author (作者) 李曉怡zh_TW
dc.contributor.author (作者) Lee, Hsiao Yien_US
dc.creator (作者) 李曉怡zh_TW
dc.creator (作者) Lee, Hsiao Yien_US
dc.date (日期) 2010en_US
dc.date.accessioned 12-四月-2012 14:12:31 (UTC+8)-
dc.date.available 12-四月-2012 14:12:31 (UTC+8)-
dc.date.issued (上傳時間) 12-四月-2012 14:12:31 (UTC+8)-
dc.identifier (其他 識別碼) G0098754005en_US
dc.identifier.uri (URI) http://nccur.lib.nccu.edu.tw/handle/140.119/52638-
dc.description (描述) 碩士zh_TW
dc.description (描述) 國立政治大學zh_TW
dc.description (描述) 神經科學研究所zh_TW
dc.description (描述) 98754005zh_TW
dc.description (描述) 99zh_TW
dc.description.abstract (摘要) 蛋白激酶 CK2 是一種具有多種功能的絲胺酸/蘇胺酸蛋白質激酶，其作用的受質眾多且普遍存在於哺乳類動物細胞中。從許多的研究結果顯示，蛋白激酶 CK2 參與調節許多的神經系統功能其中包括有神經保護作用，但是其分子層面的機制目前尚未釐清。DARPP-32（Dopamine- and cAMP-regulated phosphoprotein, Mr 32 kDa）主要表現在紋狀體中型多刺狀 GABA 神經元中的蛋白質，參與調控與藥物成癮相關的多巴胺訊息傳遞路徑，不過，近年來的一些研究報告指出DARPP-32亦參與了細胞的抗凋亡作用。雖然先前已有研究發現DARPP-32 Ser102胺基酸是CK2的磷酸化作用受質，但是並沒有進一步的研究證實，該胺基酸的磷酸化作用是否參與CK2所調控的細胞機制。屬於抗細胞凋亡蛋白Bcl-2 家族成員之ㄧ的bcl-x基因會經由pre-mRNA選擇性剪裁機制（alternative splicing）而產生兩種異構蛋白Bcl-xL和Bcl-xS，其中Bcl-xL蛋白被證實會促進細胞存活；而Bcl-xS蛋白則會造成細胞死亡。實驗室先前的研究結果發現，在神經滋養因子BDNF的刺激下，CK2可以促進Bcl-xL基因的表現，因此本論文欲進一步探討CK2對DARPP-32 Ser102的磷酸化作用是否參與CK2的抗細胞凋亡訊息傳遞，進而影響Bcl-xL和Bcl-xS的表現。實驗結果顯示，轉染野生型CK2α DNA質體會增加DARPP-32 Ser102的磷酸化現象、Bcl-xL的蛋白質表現以及Bcl-xL/Bcl-xS mRNA的比例；而處理 CK2 抑制劑 TBB 或轉染 CK2α siRNA則會降低 DARPP-32 Ser102的磷酸化現象、Bcl-xL的蛋白質表現以及Bcl-xL/Bcl-xS mRNA的比例。此外，轉染 DARPP-32 siRNA會降低 Bcl-xL的蛋白質表現。轉染模擬之磷酸化構型的DARPP-32 S102D DNA質體會增加Bcl-xL的蛋白質表現以及Bcl-xL/Bcl-xS mRNA的比例；但是，轉染突變型DARPP-32 S102A DNA質體則會降低Bcl-xL的蛋白質表現以及Bcl-xL/Bcl-xS mRNA的比例。進一步利用野生型CK2α和DARPP-32 S102A DNA質體進行細胞共同轉染的實驗結果則發現，DARPP-32 S102A會拮抗野生型 CK2α對促進Bcl-xL蛋白質表現的作用；另外，利用過氧過氫產生細胞氧化逆境下，CK2α或DARPP-32 siRNA處理可以顯著降低 DARPP-32 Ser102的磷酸化現象、Bcl-xL的蛋白質表現以及Bcl-xL/Bcl-xS mRNA的比例，同時會顯著造成細胞凋亡。綜合本論文的實驗結果，顯示CK2會透過DARPP-32 Ser102的磷酸化作用而調控Bcl-xL以及Bcl-xS的表現，而且在氧化逆境下，此條細胞訊息傳遞路徑應參與了細胞的抗凋亡機制。zh_TW
dc.description.abstract (摘要) Protein kinase CK2 is a multifunctional serine/threonine protein kinase with many protein substrares and is ubiquitously expressed in mammalian cells. Many studies have shown that CK2 is involved in many neuronal functions including neuroprotection, but its cellular mechanisms are not well-studied. DARPP-32 (Dopamine- and cAMP-regulated phosphoprotein, Mr 32 kDa) is highly enriched in striatal medium-size spiny GABA neurons and is a prominent mediator of dopamine signalling which relates with drug abuse. Beside its well-known function in drug abuse, recent studies also reveal that DARPP-32 may be involved in the anti-apoptotic effects. Although the Ser102 residue of DARPP-32 is a phosphorylation site for CK2, this phosphorylation-mediated CK2 signaling has not been studied yet. The bcl-x gene, one member of the Bcl-2 family, encodes two isoform proteins Bcl-xL and Bcl-xS by the pre-mRNA alternative splicing. The former increases cell survival and the later enhances cell apoptosis. Our previous study found that CK2 can increase Bcl-xL expression by BDNF treatment. In the present study, we investigate whether DARPP-32 ser102 phosphorylation also mediates the CK2 signaling for cell survival. Our results revealed that DARPP-32 Ser102 phosphorylation, Bcl-xL protein level and Bcl-xL/Bcl-xS mRNA ratio were all increased by wild-type CK2α plasmid DNA transfection. Meanwhile, CK2 inhibitor TBB treatment or CK2α siRNA transfection decreased DARPP-32 Ser102 phosphorylation, Bcl-xL protein level and Bcl-xL/Bcl-xS mRNA ratio. On the other hand, DARPP-32 siRNA transfection decreased Bcl-xL protein level. Furthermore, transfection of DARPP-32 S102D, which mimics the constitutive phosphorylation form, increased whereas transfection of mutant S102A decreased the Bcl-xL protein level and Bcl-xL/Bcl-xS mRNA ratio. Further, the mutant DARPP-32 S102A antagonized the up-regulatory effects of wild-type CK2α on Bcl-xL protein level in the co-transfection experiments. From the results of H2O2-induced oxidative stress experiments, we also found that prior knock-down of CK2 or DARPP-32 can aggravate the decrease in DARPP-32 Ser102 phosphorylation, Bcl-xL protein level and Bcl-xL/Bcl-xS mRNA ratio by H2O2 treatment. These results together suggest that DARPP-32 mediates CK2α signaling in regulating Bcl-xL/Bcl-xS expression and this signaling pathway might be involved in cell survival under oxidative stress.en_US
dc.description.tableofcontents 謝 誌…………………………………………………………………………………………I
     中文摘要……………………………………………………………………………………...II
     英文摘要……………………………………………………………………………………..IV
     目 錄…………………………………………….………………………………………….VI
     圖 次…………………………………………………….………………………………….IX
     縮寫表…………………………………………………………….………………………….XI
     第一章 緒 論……………………………………………………………………………..01
     第一節、蛋白激酶CK2（Protein kinase CK2, Casein kinase 2）…………...............02
     第二節、DARPP-32 (Dopamine- and cAMP-regulated phosphoprotein, Mr 32 kDa)
     ……………………………………………………………………………………..05
     第三節、計畫性的細胞凋亡 (Apoptosis)………….…………………………….............09
     第四節、Bcl-2 (B-cell lymphoma-2) 家族………..……………………………………...11
      一、Bcl-2 (B-cell lymphoma-2) 家族………………………………………………..11
      二、Bcl-xL 和 Bcl-xS………………………………………………………………...11
     第五節、論文之研究目的及策略………………………………………………................13
     第二章 實驗材料與方法………………………………………………………………….14
     第一節、細胞培養………………………………………………………………………….15
     第二節、質體製備、定點突變和萃取…………………………………………………….16
      一、質體製備………………………………………………………………………….16
      二、定點突變………………………………………………………………………….16
      三、質體之萃取……………………………………………………………………….17
      四、菌種保存………………………………………………………………………….17
     第三節、DARPP-32 S102 位置磷酸化抗體製備…………………………………….....17
     第四節、細胞轉染 ………………………..……………………………………………….17
     第五節、藥物處理…………………………………………............................................ 18
     第六節、西方點墨法………………………………………………………………………..19
     一、蛋白質萃取………………………………………………………………………..19
     二、蛋白質濃度測定…………………………………………………………………..19
     三、樣品配製…………………………………………………………………………19
     四、鑄膠和聚丙烯醯胺膠體電泳 (Sodium dodecyl sulfate polyacrylamide gel
     　 electrophoresis, SDS-PAGE)…………………………………………………..20
     五、轉漬 (transfer)…………………………………………………………………...20
     六、免疫轉印 (Immunoblotting)…………………………………………………….20
     第七節、免疫沉澱法 (Immunoprecipitation, IP)………………………………………...21
     第八節、即時定量聚合酶連鎖反應 (Quantitative real-time polymerase chain
      reaction)…………………………………………………………………………..22
      一、RNA 之萃取……………………………………………………………………...22
      二、反轉錄互補DNA (cDNA)………………………………………………………..22
      三、即時定量聚合酶連鎖反應………………………………………………………..22
     第九節、脫氧核糖核苷酸末端轉移酶介導的缺口末端標記法 (Terminal
      deoxynucleotidyl transferase–mediated dUTP nick end-labeling assay,
      TUNEL)…………………………………………………………………………...23
     第十節、統計分析………………………………………………………………................24
     第三章 實驗結果…………………………………………………………………………..25
     第一節、轉染 CK2WT DNA 質體對 DARPP-32 Ser102 磷酸化、 Bcl-xL
     蛋白質含量以及 Bcl-xL/Bcl-xS mRNA 表現的影響…………………… ……26
     第二節、CK2 抑制劑 4,5,6,7-tetrabromobenzotriazole (TBB) 對細胞 DARPP-32
      Ser102 磷酸化和 Bcl-xL 蛋白質含量以及 Bcl-xL/Bcl-xS mRNA 表現的影
     響…………………………………………………………………………………..31
     第三節、轉染 CK2 siRNA 對 DARPP-32 Ser102 的磷酸化、Bcl-xL 蛋白質含量
     以及Bcl-xL/Bcl-xS mRNA 表現的影響……………..………………………....33
     第四節、轉染DARPP-32 siRNA對DARPP-32、Bcl-xL蛋白質含量以及Bcl-xL/
     Bcl-Xs mRNA 表現的影響……………………………………………...……….37
     第五節、轉染突變型 DARPP-32 S102D和DARPP-32 S102A質體對細胞 Bcl-xL
     蛋白質含量以及Bcl-xL/Bcl-xS mRNA 表現的影響…………………………..40
     第六節、共同轉染野生型CK2WT與突變型DARPP-32 S102A DNA質體對細胞中
      Bcl-xL蛋白質含量的影響………………………………………………………45
     第七節、轉染CK2 siRNA 或 DARPP-32 siRNA 對細胞存活率影響……………....47
     第八節、轉染 CK2 siRNA 或 DARPP-32 siRNA 對過氧化氫 (Hydrogen peroxide)
      處理之細胞 DARPP-32 Ser102 的磷酸化、Bcl-xL 蛋白質含量以及
      Bcl-xL/Bcl-xS mRNA 表現的影響……………..………………………………49
     第九節、轉染 CK2 siRNA 或 DARPP-32 siRNA 對過氧化氫處理之細胞存活率的影響………………………………………………………………………………….53
     第四章 討 論…………………………………………………………………................56
     第五章 結 論……………………………………………………………………………..63
     參考文獻……………………………………………………………………………………..64
     附錄一、胜肽合成報告……………………………………………………………………..71
     附錄二、pcDNA3 載體與圖……………………………………………………………….73
     附錄三、pCMV 載體與圖……………………………………………..............................74		zh_TW
dc.language.iso en_US-
dc.source.uri (資料來源) http://thesis.lib.nccu.edu.tw/record/#G0098754005en_US
dc.subject (關鍵詞) 蛋白激酶CK2zh_TW
dc.subject (關鍵詞) DARPP-32蛋白zh_TW
dc.subject (關鍵詞) 抗細胞凋亡Bcl-xL蛋白zh_TW
dc.subject (關鍵詞) 促細胞凋亡Bcl-xS蛋白zh_TW
dc.subject (關鍵詞) 抗細胞凋亡zh_TW
dc.subject (關鍵詞) protein kinase CK2en_US
dc.subject (關鍵詞) DARPP-32en_US
dc.subject (關鍵詞) Bcl-xLen_US
dc.subject (關鍵詞) Bcl-xSen_US
dc.subject (關鍵詞) anti-apoptosisen_US
dc.title (題名) 蛋白激酶 CK2 調控受質蛋白 DARPP-32 磷酸化對 PC12 細胞株之抗凋亡機制的探討zh_TW
dc.title (題名) DARPP-32 phosphorylation by protein kinase CK2 mediates the anti-apoptotic effects in PC12 cellsen_US
dc.type (資料類型) thesisen
dc.relation.reference (參考文獻) Ahn JH, McAvoy T, Rakhilin SV, Nishi A, Greengard P, Nairn AC (2007) Protein kinase A activates protein phosphatase 2A by phosphorylation of the B56delta subunit. Proc Natl Acad Sci U S A 104:2979-2984.zh_TW
dc.relation.reference (參考文獻) Aksenova MV, Burbaeva GS, Kandror KV, Kapkov DV, Stepanov AS (1991) The decreased level of casein kinase 2 in brain cortex of schizophrenic and Alzheimer`s disease patients. FEBS Lett 279:55-57.zh_TW
dc.relation.reference (參考文獻) Apostol BL, Illes K, Pallos J, Bodai L, Wu J, Strand A, Schweitzer ES, Olson JM, Kazantsev A, Marsh JL, Thompson LM (2006) Mutant huntingtin alters MAPK signaling pathways in PC12 and striatal cells: ERK1/2 protects against mutant huntingtin-associated toxicity. Hum Mol Genet 15:273-285.zh_TW
dc.relation.reference (參考文獻) Bateup HS, Santini E, Shen W, Birnbaum S, Valjent E, Surmeier DJ, Fisone G, Nestler EJ, Greengard P (2010) Distinct subclasses of medium spiny neurons differentially regulate striatal motor behaviors. Proc Natl Acad Sci U S A 107:14845-14850.zh_TW
dc.relation.reference (參考文獻) Bateup HS, Svenningsson P, Kuroiwa M, Gong S, Nishi A, Heintz N, Greengard P (2008) Cell type-specific regulation of DARPP-32 phosphorylation by psychostimulant and antipsychotic drugs. Nat Neurosci 11:932-939.zh_TW
dc.relation.reference (參考文獻) Belkhiri A, Zaika A, Pidkovka N, Knuutila S, Moskaluk C, El-Rifai W (2005) Darpp-32: a novel antiapoptotic gene in upper gastrointestinal carcinomas. Cancer Res 65:6583-6592.zh_TW
dc.relation.reference (參考文獻) Bibb JA, Snyder GL, Nishi A, Yan Z, Meijer L, Fienberg AA, Tsai LH, Kwon YT, Girault JA, Czernik AJ, Huganir RL, Hemmings HC, Jr., Nairn AC, Greengard P (1999) Phosphorylation of DARPP-32 by Cdk5 modulates dopamine signalling in neurons. Nature 402:669-671.zh_TW
dc.relation.reference (參考文獻) Bibb JA, Yan Z, Svenningsson P, Snyder GL, Pieribone VA, Horiuchi A, Nairn AC, Messer A, Greengard P (2000) Severe deficiencies in dopamine signaling in presymptomatic Huntington`s disease mice. Proc Natl Acad Sci U S A 97:6809-6814.zh_TW
dc.relation.reference (參考文獻) Blanquet PR (1998) Neurotrophin-induced activation of casein kinase 2 in rat hippocampal slices. Neuroscience 86:739-749.zh_TW
dc.relation.reference (參考文獻) Boise LH, Gonzalez-Garcia M, Postema CE, Ding L, Lindsten T, Turka LA, Mao X, Nunez G, Thompson CB (1993) bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell 74:597-608.zh_TW
dc.relation.reference (參考文獻) Bonoiu AC, Mahajan SD, Ding H, Roy I, Yong KT, Kumar R, Hu R, Bergey EJ, Schwartz SA, Prasad PN (2009) Nanotechnology approach for drug addiction therapy: gene silencing using delivery of gold nanorod-siRNA nanoplex in dopaminergic neurons. Proc Natl Acad Sci U S A 106:5546-5550.zh_TW
dc.relation.reference (參考文獻) Boon-Unge K, Yu Q, Zou T, Zhou A, Govitrapong P, Zhou J (2007) Emetine Regulates the Alternative Splicing of Bcl-x through a Protein Phosphatase 1-Dependent Mechanism. Chem Biol 14:1386-1392.zh_TW
dc.relation.reference (參考文獻) Bredesen DE, Rao RV, Mehlen P (2006) Cell death in the nervous system. Nature 443:796-802.zh_TW
dc.relation.reference (參考文獻) Buchou T, Vernet M, Blond O, Jensen HH, Pointu H, Olsen BB, Cochet C, Issinger OG, Boldyreff B (2003) Disruption of the regulatory beta subunit of protein kinase CK2 in mice leads to a cell-autonomous defect and early embryonic lethality. Mol Cell Biol 23:908-915.zh_TW
dc.relation.reference (參考文獻) Burnett G, Kennedy EP (1954) The enzymatic phosphorylation of proteins. J Biol Chem 211:969-980.zh_TW
dc.relation.reference (參考文獻) Cash R, Raisman R, Ploska A, Agid Y (1987) Dopamine D-1 receptor and cyclic AMP-dependent phosphorylation in Parkinson`s disease. J Neurochem 49:1075-1083.zh_TW
dc.relation.reference (參考文獻) Chalfant CE, Rathman K, Pinkerman RL, Wood RE, Obeid LM, Ogretmen B, Hannun YA (2002) De novo ceramide regulates the alternative splicing of caspase 9 and Bcl-x in A549 lung adenocarcinoma cells. Dependence on protein phosphatase-1. J Biol Chem 277:12587-12595.zh_TW
dc.relation.reference (參考文獻) Chao CC, Chiang CH, Ma YL, Lee EH (2006) Molecular mechanism of the neurotrophic effect of GDNF on DA neurons: role of protein kinase CK2. Neurobiol Aging 27:105-118.zh_TW
dc.relation.reference (參考文獻) Chao CC, Ma YL, Lee EH (2011) Brain-derived neurotrophic factor enhances Bcl-xL expression through protein kinase casein kinase 2-activated and nuclear factor kappa B-mediated pathway in rat hippocampus. Brain Pathol 21:150-162.zh_TW
dc.relation.reference (參考文獻) Charriaut-Marlangue C, Otani S, Creuzet C, Ben-Ari Y, Loeb J (1991) Rapid activation of hippocampal casein kinase II during long-term potentiation. Proc Natl Acad Sci U S A 88:10232-10236.zh_TW
dc.relation.reference (參考文獻) Chester N, Yu IJ, Marshak DR (1995) Identification and characterization of protein kinase CKII isoforms in HeLa cells. Isoform-specific differences in rates of assembly from catalytic and regulatory subunits. J Biol Chem 270:7501-7514.zh_TW
dc.relation.reference (參考文獻) Cho ES, Lee KW, Lee HJ (2008) Cocoa procyanidins protect PC12 cells from hydrogen-peroxide-induced apoptosis by inhibiting activation of p38 MAPK and JNK. Mutat Res 640:123-130.zh_TW
dc.relation.reference (參考文獻) Deigner HP, Haberkorn U, Kinscherf R (2000) Apoptosis modulators in the therapy of neurodegenerative diseases. Expert Opin Investig Drugs 9:747-764.zh_TW
dc.relation.reference (參考文獻) Desagher S, Osen-Sand A, Montessuit S, Magnenat E, Vilbois F, Hochmann A, Journot L, Antonsson B, Martinou JC (2001) Phosphorylation of bid by casein kinases I and II regulates its cleavage by caspase 8. Mol Cell 8:601-611.zh_TW
dc.relation.reference (參考文獻) Desdouits F, Siciliano JC, Nairn AC, Greengard P, Girault JA (1998) Dephosphorylation of Ser-137 in DARPP-32 by protein phosphatases 2A and 2C: different roles in vitro and in striatonigral neurons. Biochem J 330 211-216.zh_TW
dc.relation.reference (參考文獻) Di Maira G, Salvi M, Arrigoni G, Marin O, Sarno S, Brustolon F, Pinna LA, Ruzzene M (2005) Protein kinase CK2 phosphorylates and upregulates Akt/PKB. Cell Death Differ 12:668-677.zh_TW
dc.relation.reference (參考文獻) Diaz-Nido J, Serrano L, Mendez E, Avila J (1988) A casein kinase II-related activity is involved in phosphorylation of microtubule-associated protein MAP-1B during neuroblastoma cell differentiation. J Cell Biol 106:2057-2065.zh_TW
dc.relation.reference (參考文獻) Doeppner TR, El Aanbouri M, Dietz GP, Weise J, Schwarting S, Bahr M (2010) Transplantation of TAT-Bcl-xL-transduced neural precursor cells: long-term neuroprotection after stroke. Neurobiol Dis 40:265-276.zh_TW
dc.relation.reference (參考文獻) Dole MG, Clarke MF, Holman P, Benedict M, Lu J, Jasty R, Eipers P, Thompson CB, Rode C, Bloch C, Nunez, Castle VP (1996) Bcl-xS enhances adenoviral vector-induced apoptosis in neuroblastoma cells. Cancer Res 56:5734-5740.zh_TW
dc.relation.reference (參考文獻) El-Rifai W, Smith MF, Jr., Li G, Beckler A, Carl VS, Montgomery E, Knuutila S, Moskaluk CA, Frierson HF, Jr., Powell SM (2002) Gastric cancers overexpress DARPP-32 and a novel isoform, t-DARPP. Cancer Res 62:4061-4064.zh_TW
dc.relation.reference (參考文獻) Fienberg AA, Greengard P (2000) The DARPP-32 knockout mouse. Brain Res Brain Res Rev 31:313-319.zh_TW
dc.relation.reference (參考文獻) Fienberg AA, Hiroi N, Mermelstein PG, Song W, Snyder GL, Nishi A, Cheramy A, O`Callaghan JP, Miller DB, Cole DG, Corbett R, Haile CN, Cooper DC, Onn SP, Grace AA, Ouimet CC, White FJ, Hyman SE, Surmeier DJ, Girault J, Nestler EJ, Greengard P (1998) DARPP-32: Regulator of the Efficacy of Dopaminergic Neurotransmission. Science 281:838-842.zh_TW
dc.relation.reference (參考文獻) Garcia-Jimenez C, Zaballos MA, Santisteban P (2005) DARPP-32 (Dopamine and 3`,5`-Cyclic Adenosine Monophosphate-Regulated Neuronal Phosphoprotein) Is Essential for the Maintenance of Thyroid Differentiation. Mol Endocrinol 19:3060-3072.zh_TW
dc.relation.reference (參考文獻) Gerfen CR, Engber TM, Mahan LC, Susel Z, Chase TN, Monsma FJ, Jr., Sibley DR (1990) D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons. Science 250:1429-1432.zh_TW
dc.relation.reference (參考文獻) Girault JA, Hemmings HC, Jr, Williams KR, Nairn AC, Greengard P (1989) Phosphorylation of DARPP-32, a dopamine- and cAMP-regulated phosphoprotein, by casein kinase II. J Biol Chem 264:21748--21759.zh_TW
dc.relation.reference (參考文獻) Girault JA, Hemmings HC, Jr., Zorn SH, Gustafson EL, Greengard P (1990) Characterization in mammalian brain of a DARPP-32 serine kinase identical to casein kinase II. J Neurochem 55:1772-1783.zh_TW
dc.relation.reference (參考文獻) Goldstein JC, Waterhouse NJ, Juin P, Evan GI, Green DR (2000) The coordinate release of cytochrome c during apoptosis is rapid, complete and kinetically invariant. Nat Cell Biol 2:156-162.zh_TW
dc.relation.reference (參考文獻) Gorman AM, McGowan A, O`Neill C, Cotter T (1996) Oxidative stress and apoptosis in neurodegeneration. J Neurol Sci 139 Suppl:45-52.zh_TW
dc.relation.reference (參考文獻) Green DR (2005) Apoptotic pathways: ten minutes to dead. Cell 121:671-674.zh_TW
dc.relation.reference (參考文獻) Green DR, Reed JC (1998) Mitochondria and apoptosis. Science 281:1309-1312.zh_TW
dc.relation.reference (參考文獻) Greene LA, Tischler AS (1976) Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Proc Natl Acad Sci U S A 73:2424-2428.zh_TW
dc.relation.reference (參考文獻) Greengard P (2001) The Neurobiology of Slow Synaptic Transmission. Science 294:1024-1030.zh_TW
dc.relation.reference (參考文獻) Greengard P, Allen PB, Nairn AC (1999) Beyond the dopamine receptor: the DARPP-32/protein phosphatase-1 cascade. Neuron 23:435-447.zh_TW
dc.relation.reference (參考文獻) Hakansson K, Galdi S, Hendrick J, Snyder G, Greengard P, Fisone G (2006) Regulation of phosphorylation of the GluR1 AMPA receptor by dopamine D2 receptors. J Neurochem 96:482-488.zh_TW
dc.relation.reference (參考文獻) Hamada M, Hendrick JP, Ryan GR, Kuroiwa M, Higashi H, Tanaka M, Nairn AC, Greengard P, Nishi A (2005) Nicotine Regulates DARPP-32 (Dopamine- and cAMP-Regulated Phosphoprotein of 32 kDa) Phosphorylation at Multiple Sites in Neostriatal Neurons. J Pharmacol Exp Ther 315:872-878.zh_TW
dc.relation.reference (參考文獻) Hemmings HC, Jr., Nairn AC, Elliott JI, Greengard P (1990) Synthetic peptide analogs of DARPP-32 (Mr 32,000 dopamine- and cAMP-regulated phosphoprotein), an inhibitor of protein phosphatase-1. Phosphorylation, dephosphorylation, and inhibitory activity. J Biol Chem 265:20369-20376.zh_TW
dc.relation.reference (參考文獻) Homma MK, Wada I, Suzuki T, Yamaki J, Krebs EG, Homma Y (2005) CK2 phosphorylation of eukaryotic translation initiation factor 5 potentiates cell cycle progression. Proc Natl Acad Sci U S A 102:15688-15693.zh_TW
dc.relation.reference (參考文獻) Izeradjene K, Douglas L, Delaney A, Houghton JA (2005) Casein kinase II (CK2) enhances death-inducing signaling complex (DISC) activity in TRAIL-induced apoptosis in human colon carcinoma cell lines. Oncogene 24:2050-2058.zh_TW
dc.relation.reference (參考文獻) Jang JH, Surh YJ (2001) Protective effects of resveratrol on hydrogen peroxide-induced apoptosis in rat pheochromocytoma (PC12) cells. Mutat Res 496:181-190.zh_TW
dc.relation.reference (參考文獻) Kim HJ, Lee KW, Kim MS, Lee HJ (2008a) Piceatannol attenuates hydrogen-peroxide- and peroxynitrite-induced apoptosis of PC12 cells by blocking down-regulation of Bcl-XL and activation of JNK. J Nutr Biochem 19:459-466.zh_TW
dc.relation.reference (參考文獻) Kim HR, Kim K, Lee KH, Kim SJ, Kim J (2008b) Inhibition of casein kinase 2 enhances the death ligand- and natural kiler cell-induced hepatocellular carcinoma cell death. Clin Exp Immunol 152:336-344.zh_TW
dc.relation.reference (參考文獻) Kluck RM, Bossy-Wetzel E, Green DR, Newmeyer DD (1997) The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis. Science 275:1132-1136.zh_TW
dc.relation.reference (參考文獻) Kuwana T, Bouchier-Hayes L, Chipuk JE, Bonzon C, Sullivan BA, Green DR, Newmeyer DD (2005) BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly. Mol Cell 17:525-535.zh_TW
dc.relation.reference (參考文獻) Laramas M, Pasquier D, Filhol O, Ringeisen F, Descotes JL, Cochet C (2007) Nuclear localization of protein kinase CK2 catalytic subunit (CK2alpha) is associated with poor prognostic factors in human prostate cancer. Eur J Cancer 43:928-934.zh_TW
dc.relation.reference (參考文獻) Letai A, Bassik MC, Walensky LD, Sorcinelli MD, Weiler S, Korsmeyer SJ (2002) Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell 2:183-192.zh_TW
dc.relation.reference (參考文獻) Liu FC, Graybiel AM (1996) Spatiotemporal dynamics of CREB phosphorylation: transient versus sustained phosphorylation in the developing striatum. Neuron 17:1133-1144.zh_TW
dc.relation.reference (參考文獻) Liu R, Page C, Beidler DR, Wicha MS, Nunez G (1999) Overexpression of Bcl-x(L) promotes chemotherapy resistance of mammary tumors in a syngeneic mouse model. Am J Pathol 155:1861-1867.zh_TW
dc.relation.reference (參考文獻) Lou DY, Dominguez I, Toselli P, Landesman-Bollag E, O`Brien C, Seldin DC (2008) The alpha catalytic subunit of protein kinase CK2 is required for mouse embryonic development. Mol Cell Biol 28:131-139.zh_TW
dc.relation.reference (參考文獻) Mahajan SD, Aalinkeel R, Reynolds JL, Nair BB, Sykes DE, Hu Z, Bonoiu A, Ding H, Prasad PN, Schwartz SA (2009a) Therapeutic targeting of "DARPP-32": a key signaling molecule in the dopiminergic pathway for the treatment of opiate addiction. Int Rev Neurobiol 88:199-222.zh_TW
dc.relation.reference (參考文獻) Mahajan SD, Aalinkeel R, Reynolds JL, Nair BB, Sykes DE, Hu Z, Bonoiu A, Ding H, Prasad PN, Schwartz SA (2009b) Therapeutic Targeting of “DARPP-32”A Key Signaling Molecule in the Dopiminergic Pathway for the Treatment of Opiate Addiction. Int Rev Neurobiol 88:199-222.zh_TW
dc.relation.reference (參考文獻) Matsura T, Kai M, Fujii Y, Ito H, Yamada K (1999) Hydrogen peroxide-induced apoptosis in HL-60 cells requires caspase-3 activation. Free Radic Res 30:73-83.zh_TW
dc.relation.reference (參考文獻) McKendrick L, Milne D, Meek D (1999) Protein kinase CK2-dependent regulation of p53 function: evidence that the phosphorylation status of the serine 386 (CK2) site of p53 is constitutive and stable. Mol Cell Biochem 191:187-199.zh_TW
dc.relation.reference (參考文獻) Meggio F, Pinna LA (2003) One-thousand-and-one substrates of protein kinase CK2? FASEB J 17:349-368.zh_TW
dc.relation.reference (參考文獻) Murnion ME, Adams RR, Callister DM, Allis CD, Earnshaw WC, Swedlow JR (2001) Chromatin-associated Protein Phosphatase 1 Regulates Aurora-B and Histone H3 Phosphorylation. J Biol Chem 276:26656-26665.zh_TW
dc.relation.reference (參考文獻) Nishi A, Bibb JA, Snyder GL, Higashi H, Nairn AC, Greengard P (2000) Amplification of dopaminergic signaling by a positive feedback loop. Proc Natl Acad Sci U S A 97:12840-12845.zh_TW
dc.relation.reference (參考文獻) Nishi A, Snyder GL, Nairn AC, Greengard P (1999) Role of calcineurin and protein phosphatase-2A in the regulation of DARPP-32 dephosphorylation in neostriatal neurons. J Neurochem 72:2015-2021.zh_TW
dc.relation.reference (參考文獻) Ouimet CC, Miller PE, Hemmings HC, Walaas SI, Greengard P (1984) DARPP-32, a dopamine- and adenosine 3`:5`-monophosphate-regulated phosphoprotein enriched in dopamine-innervated brain regions. III. Immunocytochemical localization. J Neurosci 4:111-124.zh_TW
dc.relation.reference (參考文獻) Salvesen GS, Dixit VM (1997) Caspases: intracellular signaling by proteolysis. Cell 91:443-446.zh_TW
dc.relation.reference (參考文獻) Sarno S, Reddy H, Meggio F, Ruzzene M, Davies SP, Donella-Deana A, Shugar D, Pinna LA (2001) Selectivity of 4,5,6,7-tetrabromobenzotriazole, an ATP site-directed inhibitor of protein kinase CK2 ("casein kinase-2`). FEBS Lett 496:44-48.zh_TW
dc.relation.reference (參考文獻) Schneider CC, Hessenauer A, Gotz C, Montenarh M (2009) DMAT, an inhibitor of protein kinase CK2 induces reactive oxygen species and DNA double strand breaks. Oncol Rep 21:1593-1597.zh_TW
dc.relation.reference (參考文獻) Sekharam M, Zhao H, Sun M, Fang Q, Zhang Q, Yuan Z, Dan HC, Boulware D, Cheng JQ, Coppola D (2003) Insulin-like growth factor 1 receptor enhances invasion and induces resistance to apoptosis of colon cancer cells through the Akt/Bcl-x(L) pathway. Cancer Res 63:7708-7716.zh_TW
dc.relation.reference (參考文獻) Stipanovich A, Valjent E, Matamales M, Nishi A, Ahn JH, Maroteaux M, Bertran-Gonzalez J, Brami-Cherrier K, Enslen H, Corbillé AG, Filhol O, Nairn AC, Greengard P, Hervé D, Girault JA (2008) A phosphatase cascade by which rewarding stimuli control nucleosomal response. Nature 453:879-884.zh_TW
dc.relation.reference (參考文獻) Stoof JC, Kebabian JW (1981) Opposing roles for D-1 and D-2 dopamine receptors in efflux of cyclic AMP from rat neostriatum. Nature 294:366-368.zh_TW
dc.relation.reference (參考文獻) Stumm G, Schlegel J, Schafer T, Wurz C, Mennel HD, Krieg JC, Vedder H (1999) Amphetamines induce apoptosis and regulation of bcl-x splice variants in neocortical neurons. FASEB J 13:1065-1072.zh_TW
dc.relation.reference (參考文獻) Svenningsson P, Nishi A, Fisone G, Girault J-A, Nairn AC, Greengard P (2004) DARPP-32: An Integrator of Neurotransmission. Annu Rev Pharmacol Toxicol 44:269-296.zh_TW
dc.relation.reference (參考文獻) Ulery PG, Rudenko G, Nestler EJ (2006) Regulation of FosB Stability by Phosphorylation. J Neurosci 26:5131-5142.zh_TW
dc.relation.reference (參考文獻) Valjent E, Pascoli V, Svenningsson P, Paul S, Enslen H, Corvol JC, Stipanovich A, Caboche J, Lombroso PJ, Nairn AC, Greengard P, Hervé D, Girault JA (2005) Regulation of a protein phosphatase cascade allows convergent dopamine and glutamate signals to activate ERK in the striatum. Proceedings of the National Academy of Sciences 102:491-496.zh_TW
dc.relation.reference (參考文獻) Walaas SI, Aswad DW, Greengard P (1983) A dopamine- and cyclic AMP-regulated phosphoprotein enriched in dopamine-innervated brain regions. Nature 301:69–71.zh_TW
dc.relation.reference (參考文獻) Walaas SI, Greengard p (1984) DARPP-32, a dopamine- and adenosine 3`:5`-monophosphate-regulated phosphoprotein enriched in dopamine-innervated brain regions. I. Regional and cellular distribution in the rat brain. J Neurosci 4:84-98.zh_TW
dc.relation.reference (參考文獻) Wei MC, Lindsten T, Mootha VK, Weiler S, Gross A, Ashiya M, Thompson CB, Korsmeyer SJ (2000) tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c. Genes Dev 14:2060-2071.zh_TW
dc.relation.reference (參考文獻) Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, Ross AJ, Roth KA, MacGregor GR, Thompson CB, Korsmeyer SJ (2001) Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292:727-730.zh_TW
dc.relation.reference (參考文獻) Yang H, Sadda MR, Li M, Zeng Y, Chen L, Bae W, Ou X, Runnegar MT, Mato JM, Lu SC (2004) S-adenosylmethionine and its metabolite induce apoptosis in HepG2 cells: Role of protein phosphatase 1 and Bcl-x(S). Hepatology 40:221-231.zh_TW
dc.relation.reference (參考文獻) Zachariou V, Sgambato-Faure V, Sasaki T, Svenningsson P, Berton O, Fienberg AA, Nairn AC, Greengard P, Nestler EJ (2006) Phosphorylation of DARPP-32 at Threonine-34 is required for cocaine action. Neuropsychopharmacology 31:555-562.zh_TW
dc.relation.reference (參考文獻) Zhang Y, Svenningsson P, Picetti R, Schlussman SD, Nairn AC, Ho A, Greengard P, Kreek MJ (2006) Cocaine self-administration in mice is inversely related to phosphorylation at Thr34 (protein kinase A site) and Ser130 (kinase CK1 site) of DARPP-32. J Neurosci 26:2645-2651.zh_TW
dc.relation.reference (參考文獻) Zhu S, Belkhiri A, El-Rifai W (2011) DARPP-32 Increases Interactions Between Epidermal Growth Factor Receptor and ERBB3 to Promote Tumor Resistance to Gefitinib. Gastroenterology.zh_TW