進階搜尋


 
系統識別號 U0026-0812200914082877
論文名稱(中文) 探討神經醯胺誘發細胞凋亡的訊息傳遞機轉
論文名稱(英文) Study on Signal Transduction in Ceramide-induced Apoptosis
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 96
學期 2
出版年 97
研究生(中文) 陳嘉玲
研究生(英文) Chia-Ling Chen
學號 s5891103
學位類別 博士
語文別 英文
論文頁數 126頁
口試委員 指導教授-林以行
召集委員-楊倍昌
口試委員-湯銘哲
口試委員-蔣輯武
口試委員-林銘德
口試委員-賴明宗
中文關鍵字 細胞凋亡  神經醯胺  去磷酸化酵素2A 
英文關鍵字 Ceramide  PP2A  Txnip  Apoptosis 
學科別分類
中文摘要 神經醯胺(ceramide)是磷脂質代謝產物,經由神經磷脂水解或新合成作用生成,參與調控細胞增生、分化以及凋亡。許多死亡刺激如腫瘤壞死因子、化學治療藥物、紫外線、熱休克、過氧化氫以及放射線等,皆伴隨ceramide的生成。先前的研究證實caspase-2及caspase-8順序性的活化參與調節ceramide引發的粒線體凋亡。受到ceramide調控而活化的去磷酸化酵素2A (PP2A)會導致Bcl-2去磷酸化、並誘發caspase-2活化。此外,肝醣合成激酶(GSK-3)也會參與調節caspase-2活化及粒線體凋亡。鋰鹽 (LiCl) 是一種常用於許多神經性疾病如躁鬱症以及神經退化性疾病的臨床藥物,一般被認為能對細胞提供保護以抵抗外來的刺激的功能。研究顯示LiCl能藉由抑制PP2A的活化,進而抑制ceramide及etoposide引發的凋亡。而過量表現PP2A所引發的caspase-2活化、粒線體的破壞,以及細胞凋亡的現象,皆能有效地被LiCl與PP2A抑制。在LiCl與PP2A共同處理下,ceramide及etoposide引發Bcl-2 serine70位置的去磷酸化現象亦會被回復。進一步發現,ceramide及etoposide的刺激會造成PP2A C subunit甲基化程度增加,促使PP2A B subunit更加結合至PP2A複合體中,使得PP2A有效活化。有趣的是,不同於OA能直接抑制PP2A活性區的機制,LiCl即是利用參與負向調節PP2A甲基化程度以及與B subunit結合作用,進以抑制ceramide引發的PP2A活化。因此,LiCl的抗凋亡作用會經由抑制PP2A的甲基化(活化),進以維持Bcl-2 的磷酸化,阻斷ceramide引發的caspase-2活化以及粒線體凋亡發生。儘管許多機制已經被提出,然而蛋白質轉錄及轉譯作用的參與機制,在ceramide誘發細胞凋亡的發生過程中所扮演的角色仍然不清楚。實驗結果證實,蛋白質轉錄機制的抑制劑actinomycin D能有效的抑制ceramide引發的細胞凋亡。根據microarray的分析結果顯示,ceramide的處理會刺激腫瘤抑制基因thioredoxin-interacting protein (Txnip)的高度表現。相同的,抗癌藥物etoposide也會透過刺激內生性ceramide的合成,促使Txnip蛋白質表現增高,進而引發細胞凋亡發生。分析顯示ceramide引發Txnip的表現會與thioredoxin co-localize在一起,並且抑制thioredoxin的還原能力,導致thioredoxin釋放apoptosis signal-regulating kinase 1 (ASK1)活化。而受ceramide刺激而活化的ASK1會進一步調節p38 MAPK 和 JNK的活化。ASK1基因剔除的細胞能抵抗ceramide的死亡刺激,抑制p38 MAPK 和 JNK的活化亦能部份阻斷ceramide引發的粒線體凋亡發生。除此之外,Txnip基因的剔除會有效地影響p38 MAPK 和 JNK的活化。上述的實驗結果顯示,ceramide會透過調節蛋白質轉錄機制刺激Txnip表現,進而活化ASK1導致p38 MAPK 和 JNK磷酸化,促使細胞凋亡發生;etoposide亦會調控如此機轉。綜而言之,ceramide能夠同時利用非蛋白質轉錄調節機制:例如修飾PP2A的活化,以及蛋白質轉錄調節機制:例如刺激Txnip的表現,來傳遞凋亡的訊息,調控細胞凋亡的發生。
英文摘要 Ceramide, a product of sphingolipid metabolism via sphingomyelin hydrolysis or de novo synthesis, regulates diverse cellular responses, including proliferation, differentiation, and apoptosis. Various apoptotic stimuli such as TNF-alpha, chemotherapeutic drugs, UV, heat shock, H2O2, and irradiation can cause accumulation of ceramide. We previously showed an essential role of caspase-2 and -8 activation in ceramide-induced mitochondrial apoptosis. Ceramide caused Bcl-2 dephosphorylation by protein phosphatase 2A (PP2A), which led to Bcl-2 inactivation and caspase-2 activation. The requirement of glycogen synthase kinase-3 (GSK-3) in ceramide-induced caspase-2 activation and mitochondrial apoptosis was verified. Lithium, a drug widely used for bipolar disorders and other neurodegenerative disorders, confers cell protection against stress and toxic stimuli. Lithium exhibits an anti-apoptotic effect on the blockage of ceramide- and etoposide-induced apoptosis via inhibition of PP2A activity. Overexpression of PP2A resulted in caspase-2 activation, mitochondrial damage, and cell apoptosis that were inhibited by okadaic acid (OA) and lithium. Lithium and OA abrogated ceramide- and etoposide-induced Bcl-2 dephosphorylation at serine 70. Furthermore, ceramide- and etoposide-induced PP2A activation involved methylation of PP2A C subunit, which lithium suppressed. Lithium caused dissociation of PP2A B subunit from the PP2A core enzyme, whereas ceramide caused recruitment of the B subunit. Therefore, lithium exhibited an anti-apoptotic effect by inhibiting ceramide-induced Bcl-2 dephosphorylation and caspase-2 activation, which involved, at least in part, a mechanism of downregulating PP2A methylation and PP2A activity. Furthermore, ceramide-mediated transcription-dependent effects on the apoptotic signaling pathways remain unclear. Our data showed that actinomycin D partially inhibited ceramide-induced apoptosis. Using microarray analysis, we found that ceramide up-regulated a tumor suppressor gene thioredoxin-interacting protein (Txnip). Similarly, the chemotherapeutic agent etoposide induced Txnip expression en route to apoptosis, which was blocked by inhibitors of ceramide production. Txnip co-localized with thioredoxin and reduced its activity, which caused dissociation of thioredoxin from ASK1. Cells expressing ASK1 siRNA were more resistant to ceramide-induced apoptosis. Ceramide caused ASK1-regulated p38 MAPK and JNK activation, and inhibition of p38 MAPK or JNK partially reduced ceramide-induced mitochondria-mediated apoptosis. In addition, ceramide-induced ASK1, p38 and JNK phosphorylation and cell apoptosis were inhibited by Txnip siRNA transfection. Ceramide exhibits a mechanism of transcriptional regulation involving up-regulation of Txnip expression, also induced by etoposide, which results in ASK1 activation, and p38 and JNK phosphorylation, all leading to apoptosis. Taken together, ceramide regulates both transcription-independent pathway via PP2A modification and transcription-dependent pathway via Txnip expression to induce cell apoptosis.
論文目次 Abstract……………………………………………………………….. I
Chinese abstract…………………………………………………......... III
Contents………………………………………………………………V
Table……………………………………………………………………X
Figure lists……………………………………………………………... XI
Abbreviations………………………………………………………….. XIV
Introduction…………………………………………………………… 1
Foreword……………………………………………………………….. 1
Mitochondria-mediated apoptosis……………………………………… 1
Ceramide-regulated apoptosis………………………………………….. 3
Mitogen-activated protein kinases……………………………………... 7
Thioredoxin-interacting protein………………………………………... 8
Lithium…………………………………………………………………. 10
Protein phosphatase 2A………………………………………………… 11
Objective and Specific aims…………………………………………... 14
Materials and Methods……………………………………………….. 16
I. Materials…………………………………………………………….. 16
Cell cultures……………………………………………………………. 16
Reagents………………………………………………………………... 16
II Methods……………………………………………………………... 17
Part A…………………………………………………………………... 17
Analysis of apoptosis…………………………………………………... 17
Mitochondrial functional assay………………………………………… 17
Detection of caspase activation………………………………………… 18
Western blot analysis…………………………………………………… 18
Protein transfection…………………………………………………….. 19
Immunostaining………………………………………………………… 20
Immunoprecipitation…………………………………………………… 21
PP2A Activity Assay and Cell-free In Vitro Phosphatase Assay……….. 21
Part B…………………………………………………………………... 22
Analysis of cell apoptosis and mitochondrial functional assay………... 22
cDNA microarray………………………………………………………. 23
Total RNA extraction and RT-PCR…………………………………….. 24
Thioredoxin activity assay……………………………………………... 24
Immunoprecipitation and Western blot analysis……………………….. 25
Short interfering RNA (siRNA) preparation and transient expression… 26
Immunostaining………………………………………………………… 27
Measurement of intracellular ROS……………………………………... 28
Statistical analysis……………………………………………………… 28
Results…………………………………………………………………. 30
Part A. Ceramide induces transcription-independent apoptotic signaling………………………………………………………
30
A-1 Lithium rescues ceramide- and etoposide-induced PP2A-mediated mitochondrial apoptosis………………………..
30
A-2 Lithium rescues ceramide- and etoposide-induced bcl-2 dephosphorylation……………………………………………….
33
A-3 Lithium inhibits PP2A indirectly……………………………….. 33
A-4 Lithium suppresses PP2A through PP2A C subunit demethylation and B subunit dissociation……………………….
34
Part B. Ceramide induces transcription-dependent apoptotic signaling……………………………………………………….
36
B-1 Actinomycin D reduces ceramide-induced apoptosis…………... 36
B-2 Microarray analysis reveals Txnip up-regulation after ceramide stimulation……………………………………………………….
37
B-3 Ceramide-upregulated Txnip co-localizes with thioredoxin and decreases its activity……………………………………………..
37
B-4 Etoposide causes ceramide generation and Txnip expression….. 38
B-5 Ceramide causes ASK1 activation……………………………… 39
B-6 p38 MAPK and JNK activation in ceramide-induced apoptotic pathway is transcription-dependent……………………………...
40
B-7 Txnip is involved in ceramide-induced p38 MAPK and JNK phosphorylation and cell death…………………………………..
42
Discussion……………………………………………………………… 44
PP2A regulates ceramide-mediated apoposis…………………………... 44
Txnip functions as a tumor suppressor…………………………………. 46
The role of ROS in ceramide signaling………………………………… 47
ASK1/p38 MAPK/JNK signaling……………………………………… 48
Transcription mechanism of Txnip……………………………………... 50
Additional signalings in ceramide-mediated apoptosis………………… 51
Conclusion……………………………………………………………... 54
References……………………………………………………………... 56
Table…………………………………………………………………… 75
Figures and Figure legends…………………………………………… 76
Appendix………………………………………………………………. 123
Publications……………………………………………………………. 126
參考文獻 Adam D, Heinrich M, Kabelitz D, Schutze S. Ceramide: does it matter for T cells? Trends Immunol. 2002;23:1.
Alavi AS, Acevedo L, Min W, Cheresh DA. Chemoresistance of endothelial cells induced by basic fibroblast growth factor depends on Raf-1-mediated inhibition of the proapoptotic kinase, ASK1. Cancer Res. 2007;67:2766.
Alvarez G, Montano JRM, Satrustegui J, Avila J, Bobonez E, Nido JD. Regulation of tau phosphorylation and protection against -amyloid-induced neurodegeneration by lithium. Possible implications for Alzheimer’s disease. Bipolar Disord. 2002;4:153.
Barnes PJ. Ceramide lances the lungs. Nat Med. 2004;10:130.
Basu S, Bayoumy S, Zhang Y, Lozano J, Kolesnick R. BAD enables ceramide to signal apoptosis via Ras and Raf-1. J Biol Chem. 1998;273:30419.
Bialojan C, Takai A. Inhibitory effect of a marine-sponge toxin, okadaic acid, on protein phosphatases. Specificity and kinetics. Biochem J. 1988;256:283.
Bijur GN, De Sarno P, Jope RS. Glycogen synthase kinase-3 facilitates staurosporine- and heat shock-induced apoptosis. Protection by lithium. J Biol Chem. 2000;275:7583.
Birbes H, Bawab SE, Obeid LM, Hannun YA. Mitochondria and ceramide: intertwined roles in regulation of apoptosis. Advan Enzyme Regul. 2002;42:113.
Bishopric NH, Webster KA. Preventing apoptosis with thioredoxin: ASK me how. Circ Res. 2002;90:1237.
Boesen-de Cock JG, Tepper AD, de Vries E, van Blitterswijk WJ, Borst J. Common regulation of apoptosis signaling induced by CD95 and the DNA-damaging stimuli etoposide and gamma-radiation downstream from caspase-8 activation. J Biol Chem. 1999;274:14255.
Bossy-Wetzel E, Green DR. Caspases induce cytochrome c release from mitochondria by activating cytosolic factors. J Biol Chem. 1999;274:17484.
Breckenridge DG, Germain M, Mathai JP, Nguyen M, Shore GC. Regulation of apoptosis by endoplasmic reticulum pathways. Oncogene. 2003;22:8608. Review.
Brenner C, Cadiou H, Vieira HL, Zamzami N, Marzo I, Xie Z, Leber B, Andrews D, Duclohier H, Reed JC, Kroemer G. Bcl-2 and Bax regulate the channel activity of the mitochondrial adenine nucleotide translocator. Oncogene. 2000;19:329.
Brummelkamp TR, Bernards R, Agami R. A system for stable expression of short interfering RNAs in mammalian cells. Science. 2002;296:550-553.
Bryant JC, Westphal RS, Wadzinski BE. Methylated C-terminal leucine residue of PP2A catalytic subunit is important for binding of regulatory B subunit. Biochem J. 1999;339:241.
Butler LM, Zhou X, Xu WS, Scher HI, Rifkind RA, Marks PA, Richon VM. The histone deacetylase inhibitor SAHA arrests cancer cell growth, up-regulates thioredoxin-binding protein-2, and down-regulates thioredoxin. Proc Natl Acad Sci USA. 2002;99:11700.
Capano M, Crompton M. Bax translocates to mitochondria of heart cells during simulated ischaemia: involvement of AMP-activated and p38 mitogen-activated protein kinases. Biochem J. 2006;395:57.
Caricchio R, D’Adamio L, Cohen PL. Fas, ceramide and serum withdrawal induce apoptosis via a common pathway in a type II Jurkat cell line. Cell Death Differ. 2002;9:574.
Chalecka-Franaszek E, Chuang DM. Lithium activates the serine/threonine kinase Akt-1 and suppresses glutamate-induced inhibition of Akt-1 activity in neurons. Proc Natl Acad Sci USA. 1999;96:8745.
Chalfant AM, Bryant RA, Fulcher G. Posttraumatic stress disorder following diagnosis of multiple sclerosis. J Trauma Stress. 2004;17:423.
Chen CL, Lin CF, Chiang CW, Jan MS, Lin YS. Lithium inhibits ceramide- and etoposide-induced protein phosphatase 2A methylation, Bcl-2 dephosphorylation, caspase-2 activation, and apoptosis. Mol Pharmacol. 2006;70:510.
Chen J, Martin BL, Brautigan DL. Regulation of protein serine-threonine phosphatase type-2A by tyrosine phosphorylation. Science. 1992;257:1261.
Chen KS, DeLuca HF. Isolation and characterization of a novel cDNA from HL-60 cells treated with 1,25-dihydroxyvitamin D-3. Biochim Biophys Acta. 1994;1219:26-32.
Chen RW, Chuang DM. Long term lithium treatment suppresses p53 and Bax expression but increases Bcl-2 expression. A prominent role in neuroprotection against excitotoxicity. J Biol Chem. 1999;274:6039.
Chmura SJ, Nodzenski E, Kharbanda S, Pandey P, Quintans J, Kufe DW, Weichselbaum RR. Down-regulation of ceramide production abrogates ionizing radiation-induced cytochrome c release and apoptosis. Mol Pharmacol. 2000;57:792.
Choi SY, Kim MJ, Kang CM, Bae S, Cho CK, Soh JW, Kim JH, Kang S, Chung HY, Lee YS, Lee SJ. Activation of Bak and Bax through c-Abl-protein kinase C-p38 MAPK signaling in response to ionizing radiation in human non-small cell lung cancer cells. J Biol Chem. 2006;281:7049.
Claus R, Russwurm S, Meisner M, Kinscherf R, Deigner HP. Modulation of the ceramide level, a novel therapeutic concept? Curr Drug Targets. 2000;1:185.
Claus RA, Bunck AC, Bockmeyer CL, Brunkhorst FM, Losche W, Kinscherf R, Deigner HP. Role of increased sphingomyelinase activity in apoptosis and organ failure of patients with severe sepsis. FASEB J. 2005;19:1719.
Cuvillier O, Nava VE, Murthy SK, Edsall LC, Levade T, Milstien S, Spiegel S. Sphingosine generation, cytochrome c release, and activation of caspase-7 in doxorubicin-induced apoptosis of MCF7 breast adenocarcinoma cells. Cell Death Differ. 2001;8:162.
Deigner HP, Claus R, Bonaterra GA, Gehrke C, Bibak N, Blaess M, Cantz M, Metz J, Kinscherf R. Ceramide induces aSMase expression: implications for oxLDL-induced apoptosis. FASEB J. 2001;807:14.
Dent P, Yacoub A, Fisher PB, Hagan MP, Grant S. MAPK pathways in radiation responses. Oncogene. 2003;22:5885. Review.
Delogu G, Famularo G, Amati F, Signore L, Antonucci A, Trinchieri V, Di Marzio L, Cifone MG. Ceramide concentrations in septic patients: a possible marker of multiple organ dysfunction syndrome. Crit Care Med. 1999;27:2413.
Desagher S, Osen-Sand A, Nichols A, Eskes R, Montessuit S, Lauper S, Maundrell K, Antonsson B, Martinou JC. Bid-induced conformational change of Bax is responsible for mitochondrial cytochrome c release during apoptosis. J. Cell Biol. 1999;144:891.
Di Pietro R, Centurione L, Sabatini N, Bosco D, Sancilio S, Garaci F, Rana R, Cataldi A. Caspase-3 is dually regulated by apoptogenic factors mitochondrial release and by SAPK/JNK metabolic pathway in leukemic cells exposed to etoposide-ionizing radiation combined treatment. Int J Immunopathol Pharmacol. 2004;17:181.
Dobrowsky RT, Kamibayashi C, Mumby MC, Hannun YA. Ceramide activates heterotrimeric protein phosphatase 2A. J Biol Chem. 1993;268:15523.
Farley N, Pedraza-Alva G, Serrano-Gomez D, Nagaleekar V, Aronshtam A, Krahl T, Thornton T, Rincon M. p38 Mitogen-activated protein kinase mediates the Fas-induced mitochondrial death pathway in CD8+ T cells. Mol Cell Biol. 2006;26:2118.
Favre B, Zolnierowicz S, Turowski P, Hemmings BA. The catalytic subunit of protein phosphatase 2A is carboxyl-methylated in vivo. J Biol Chem. 1994;269:16311-16317.
Ferraro C, Quemeneur L, Fournel S, Prigent AF, Revillard JP, Bonnefoy-Berard N. The topoisomerase inhibitors camptothecin and etoposide induce a CD95-independent apoptosis of activated peripheral lymphocytes. Cell Death Differ. 2000;7:197.
Gallo KA, Johnson GL. Mixed-lineage kinase control of JNK and p38 MAPK pathways. Nat Rev Mol Cell Biol. 2002;3:663. Review.
Goggel R, Winoto-Morbach S, Vielhaber G, Imai Y, Lindner K, Brade L, Brade H, Ehlers S, Slutsky AS, Schutze S, Gulbins E, Uhlig S. PAF-mediated pulmonary edema: a new role for acid sphingomyelinase and ceramide. Nat Med. 2004;10:155.
Goldberg B, Stricker RB. Apoptosis and HIV infection: T-cells fiddle while the immune system burns. Immunology Lett. 1999;70:5.
Gould TD, Manji HK. Glycogen synthase kinase-3: a putative molecular target for lithium mimetic drugs. Neuropsychopharmacology. 2005;30:1223. Review.
Green DR, Reed JC. Mitochondria and apoptosis. Science. 1998;281:1309.
Gulbins E. Regulation of death receptor signaling and apoptosis by ceramide. Pharmacol Res. 2003;47:393.
Gutiérrez G, Mendoza C, Montaño LF, López-Marure R. Ceramide induces early and late apoptosis in human papilloma virus+ cervical cancer cells by inhibiting reactive oxygen species decay, diminishing the intracellular concentration of glutathione and increasing nuclear factor-kappaB translocation. Anticancer Drugs. 2007;18:149.
Guo Y, Srinivasula SM, Druilhe A, Fernandes-Alnemri T, Alnemri ES. Caspase-2 induces apoptosis by releasing proapoptotic proteins from mitochondria. J Biol Chem. 2002;277:13430.
Han SH, Jeon JH, Ju HR, Jung U, Kim KY, Yoo HS, Lee YH, Song KS, Hwang HM, Na YS, Yang Y, Lee KN, Choi I. VDUP1 upregulated by TGF-1 and 1,25-dihydorxyvitamin D3 inhibits tumor cell growth by blocking cell-cycle progression. Oncogene. 2003;22:4035.
Hannun YA, Luberto C. Ceramide in the eukaryotic stress response. Trends Cell Biol. 2000;10:73.
Hannun YA, Obeid LM. Ceramide: an intracellular signal for apoptosis. Trends Biochem Sci. 1995;20:73.
Hastie CJ, Cohen PT. Purification of protein phosphatase 4 catalytic subunit: inhibition by the antitumour drug fostriecin and other tumour suppressors and promoters. FEBS Lett. 1998;431:357.
Hatai T, Matsuzawa A, Inoshita S, Mochida Y, Kuroda T, Sakamaki K, Kuida K, Yonehara S, Ichijo H, Takeda K. Execution of apoptosis signal-regulating kinase 1 (ASK1)-induced apoptosis by the mitochondria-dependent caspase activation. J Biol Chem. 2000;275:26576.
Haviv R, Lindenboim L, Yuan J, Stein R. Need for caspase-2 in apoptosis of growth-factor-deprived PC12 cells. J Neurosci Res. 1998;52:491.
Herr I, Debatin KM. Cellular stress response and apoptosis in cancer therapy. Blood. 2001;98:2603.
Holmgren A. Glutaredoxin from Escherichia coli and calf thymus. Methods Enzymol. 1985;113:525.
Holmgren A, Bjornstedt M. Thioredoxin and thioredoxin reductase. Methods Enzymol. 1995;252:199.
Horton JW. Tumor necrosis factor-alpha, sphingosine, ceramide: which is the appropriate marker of inflammation? Crit Care Med. 1999;27:2580.
Hreniuk D, Garay M, Gaarde W, Monia BP, McKay RA, Cioffi CL. Inhibition of c-Jun N-terminal kinase 1, but not c-Jun N-terminal kinase 2, suppresses apoptosis induced by ischemia/reoxygenation in rat cardiac myocytes. Mol Pharmacol. 2001;59:867.
Ichijo H, Nishida E, Irie K, ten Dijke P, Saitoh M, Moriguchi T, Takagi M, Matsumoto K, Miyazono K, Gotoh Y. Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science. 1997;275:90.
Iwai K, Kondo T, Watanabe M, Yabu T, Kitano T, Taguchi Y, Umehara H, Takahashi A, Uchiyama T, Okazaki T. Ceramide increases oxidative damage due to inhibition of catalase by caspase-3-dependent proteolysis in HL-60 cell apoptosis. J Biol Chem. 2003;278:9813.
Iwanaga N, Kamachi M, Aratake K, Izumi Y, Ida H, Tanaka F, Tamai M, Arima K, Nakamura H, Origuchi T, Kawakami A, Eguchi K. Regulation of alternative splicing of caspase-2 through an intracellular signaling pathway in response to pro-apoptotic stimuli. J Lab Clin Med. 2005;45:105.
Johnson GL, Lapadat R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science. 2002;298:1911. Review.
Jiang M, Milner J. Bcl-2 constitutively suppresses p53-dependent apoptosis in colorectal cancer cells. Genes Dev. 2003;17:832.
Ju TC, Chen SD, Liu CC, Yang DI. Protective effects of S-nitrosoglutathione against amyloid -peptide neurotoxicity. Free Radic Biol Med. 2005;38:938.
Junn E, Han SH, Im JY, Yang Y, Cho EW, Um HD, Kim DK, Lee KW, Han PL, Rhee SG, Choi I. Vitamin D3 up-regulated protein 1 mediates oxidative stress via suppressing the thioredoxin function. J Immunol. 2000;164:6287.
Kalli KR, Devine KE, Cabot MC, Arnt CR, Heldebrant MP, Svingen PA, Erlichman C, Hartmann LC, Conover CA, Kaufmann SH. Heterogeneous role of caspase-8 in fenretinide-induced apoptosis in epithelial ovarian carcinoma cell lines. Mol Pharmacol. 2003;64:1434.
Kaimul AM, Nakamura H, Masutani H, Yodoi J. Thioredoxin and thioredoxin-binding protein-2 in cancer and metabolic syndrome. Free Radic Biol Med. 2007;43:861. Review.
Kamibayashi C, Estes R, Lickteig RL, Yang SI, Craft C, Mumby MC. Comparison of heterotrimeric protein phosphatase 2A containing different B subunits. J Biol Chem. 1994;269:20139.
Kawatani M, Simizu S, Osada H, Takada M, Arber N, Imoto M. Involvement of protein kinase C-regulated ceramide generation in inostamycin-induced apoptosis. Exp Cell Res. 2000;259:389.
Kim AH, Khursigara G, Sun X, Franke TF, Chao MV. Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1. Mol Cell Biol. 2001;21:893.
Kim KY, Shin SM, Kim JK, Paik SG, Yang Y, Choi I. Heat shock factor regulates VDUP1 gene expression. Biochem Biophys Res Commun. 2004;315:369.
Kim HJ, Oh JE, Kim SW, Chun YJ, Kim MY. Ceramide induces p38 MAPK-dependent apoptosis and Bax translocation via inhibition of Akt in HL-60 cells. Cancer Lett. 2008;260:88.
Kloeker S, Reed R, McConnell JL, Chang D, Tran K, Westphal RS, Law BK, Colbran RJ, Kamoun M, Campbell KS, Wadzinski BE. Parallel purification of three catalytic subunits of the protein serine/threonine phosphatase 2A family (PP2A(C), PP4(C), and PP6(C)) and analysis of the interaction of PP2A(C) with alpha4 protein. Protein Expression Purif. 2003;31:19.
Kok JW, Sietsma H. Sphingolipid metabolism enzymes as targets for anticancer therapy. Curr Drug Targets. 2004;5:375.
Kolesnick R, Altieri D, Fuks Z. A CERTain role for ceramide in taxane-induced cell death. Cancer Cell. 2007;11:473.
Kolesnick R, Fuks Z. Radiation and ceramide-induced apoptosis. Oncogene. 2003;22:5897.
Kondo N, Ishii Y, Kwon YW, Tanito M, Horita H, Nishinaka Y, Nakamura H, Yodoi J. Redox-sensing release of human thioredoxin from T lymphocytes with negative feedback loops. J Immunol. 2004;172:442.
Kong JY, Klassen SS, Rabkin SW. Ceramide activates a mitochondrial p38 mitogen-activated protein kinase: a potential mechanism for loss of mitochondrial transmembrane potential and apoptosis. Mol Cell Biochem. 2005;278:39.
Kowluru A, Metz SA. Ceramide-activated protein phosphatase-2A activity in insulin-secreting cells. FEBS Lett. 1997;418:179.
Kowluru A, Seavey SE, Rabaglia ME, Nesher R, Metz SA. Carboxylmethylation of the catalytic subunit of protein phosphatase 2A in insulin-secreting cells: evidence for functional consequences on enzyme activity and insulin secretion. Endocrinology. 1996;137:2315.
Kroemer G, Reed JC. Mitochondrial control of cell death. Nat Med. 2000;6:513.
Kumar S, Vaux DL. A cinderella caspase takes center stage. Science. 2002;297:1290.
Kurinna SM, Tsao CC, Nica AF, Jiffar T, Ruvolo PP. Ceramide promotes apoptosis in lung cancer-derived A549 cells by a mechanism involving c-Jun NH2-terminal kinase. Cancer Res. 2004;64:7852.
Lacour S, Hammann A, Grazide S, Lagadic-Gossmann D, Athias A, Sergent O, Laurent G, Gambert P, Solary E, Dimanche-Boitrel MT. Cisplatin-induced CD95 redistribution into membrane lipid rafts of HT29 human colon cancer cells. Cancer Res. 2004;64:3593.
Lassus P, Opitz-Araya X, Lazebnik Y. Requirement for caspase-2 in stress-induced apoptosis before mitochondrial permeabilization. Science. 2002;297:1352.
Lawen A. Apoptosis-an introduction. Bioessays. 2003;25:888.
Lechward K, Awotunde OS, Swiatek W, Muszynska G. Protein phosphatase 2A: variety of forms and diversity of functions. Acta Biochim Pol. 2001;48:921.
Leducq N, Macouillard-Poulletier de Gannes F, Rotureau MA, Belloc F, Voisin P, Canioni P, Diolez P. Top down analysis ceramide-induced mitochondrial dysfunctions: role of mitochondrial swelling. Mol Biol Rep. 2002;29:47.
Lee J, Stock J. Protein phosphatase 2A catalytic subunit is methyl-esterified at its carboxyl terminus by a novel methyltransferase. J Biol Chem. 1993;268:19192.
Lee J, Chen Y, Tolstykh T, Stock J. A specific protein carboxyl methylesterase that demethylates phosphoprotein phosphatase 2A in bovine brain. Proc Natl Acad Sci USA. 1996;93:6043.
Lee JY, Hannun YA, Obeid LM. Functional dichotomy of protein kinase C (PKC) in tumor necrosis factor- (TNF-) signal transduction in L929 cells. Translocation and inactivation of PKC by TNF-. J Biol Chem. 2000;275:29290.
Li H, Zhu H, Xu CJ, Yuan J. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell. 1998;94:491.
Lin CF, Chen CL, Chang WT, Jan MS, Hsu LJ, Wu RH, Tang MJ, Chang WC, Lin YS. Sequential caspase-2 and caspase-8 activation upstream of mitochondria during ceramide- and etoposide-induced apoptosis. J Biol Chem. 2004;279:40755.
Lin CF, Chen CL, Chang WT, Jan MS, Hsu LJ, Wu RH, Fang YT, Tang MJ, Chang WC, Lin YS. Bcl-2 rescues ceramide- and etoposide-induced mitochondrial apoptosis through blockage of caspase-2 activation. J Biol Chem. 2005;280:23758.
Lin CF, Chen CL, Lin YS. Ceramide in apoptotic signaling and anticancer therapy. Curr Med Chem. 2006;13:1609.
Lin CF, Chen CL, Chiang CW, Jan MS, Huang WC, Lin YS. GSK-3 acts downstream of PP2A and the PI 3-kinase-Akt pathway, and upstream of caspase-2 in ceramide-induced mitochondrial apoptosis. J Cell Sci. 2007;120:2935.
Liu Y, Min W. Thioredoxin promotes ASK1 ubiquitination and degradation to inhibit ASK1-mediated apoptosis in a redox activity-independent manner. Circ Res. 2002;90:1259.
Ludwig DL, Kotanides H, Le T, Chavkin D, Bohlen P, Witte L. Cloning, genetic characterization, and chromosomal mapping of the mouse VDUP1 gene. Gene. 2001;269:103.
Macchia M, Bertini S, Fogli S, Giovannetti E, Minutolo F, Rapposelli S, Danesi R. Ceramide analogues in apoptosis: a new strategy for anticancer drug development. Farmaco. 2003;58:205.
Marchesini N, Hannun YA. Acid and neutral sphingomyelinases: roles and mechanisms of regulation. Biochem Cell Biol. 2004;82:27. Review.
Mathias S, Pena LA, Kolesnick RN. Signal transduction of stress via ceramide. Biochem J. 1998;335:465.
Matsukawa J, Matsuzawa A, Takeda K, Ichijo H. The ASK1-MAP kinase cascades in mammalian stress response. J Biochem (Tokyo). 2004;136:261.
Millward TA, Zolnierowicz S, Hemmings BA. Regulation of protein kinase cascades by protein phosphatase 2A. Trends Biochem Sci. 1999;24:186.
Minn AH, Hafele C, Shalev A. Thioredoxin-interacting protein is stimulated by glucose through a carbohydrate response element and induces -cell apoptosis. Endocrinology. 2005;146:2397.
Modrak DE, Gold DV, Goldenberg DM. Sphingolipid targets in cancer therapy. Mol Cancer Ther. 2006;5:200.
Mora A, Sabio G, Risco AM, Cuenda A, Alonso JC, Soler G, Centeno F. Lithium blocks the PKB and GSK3 dephosphorylation induced by ceramide through protein phosphatase-2A. Cell Signal. 2002;14:557.
Mourtada-Maarabouni M, Kirkham L, Jenkins B, Rayner J, Gonda TJ, Starr R, Trayner I, Farzaneh F, Williams GT. Functional expression cloning reveals proapoptotic role for protein phosphatase 4. Cell Death Differ. 2003;10:1016.
Nishitoh H, Matsuzawa A, Tobiume K, Saegusa K, Takeda K, Inoue K, Hori S, Kakizuka A, Ichijo H. ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. Genes Dev. 2002;16:1345.
Nishiyama A, Matsui M, Iwata S, Hirota K, Masutani H, Nakamura H, Takagi Y, Sono H, Gon Y, Yodoi J. Identification of thioredoxin-binding protein-2/vitamin D3 up-regulated protein 1 as a negative regulator of thioredoxin function and expression. J Biol Chem. 1999;274:21645.
Nishiyama A, Masutani H, Nakamura H, Nishinaka Y, Yodoi J. Redox regulation by thioredoxin and thioredoxin-binding proteins. IUBMB Life. 2001;52:29.
Noguchi T, Takeda K, Matsuzawa A, Saegusa K, Nakano H, Gohda J, Inoue J, Ichijo H. Recruitment of tumor necrosis factor receptor-associated factor family proteins to apoptosis signal-regulating kinase 1 signalosome is essential for oxidative stress-induced cell death. J Biol Chem. 2005;280:37033.
Ogretmen B, Hannun YA. Biologically active sphingolipids in cancer pathogenesis and treatment. Nat Rev Cancer. 2004;4:604.
Ogris E, Gibson DM, Pallas DC. Protein phosphatase 2A subunit assembly: the catalytic subunit carboxy terminus is important for binding cellular B subunit but not polyomavirus middle tumor antigen. Oncogene. 1997;15:911.
Patwari P, Higgins LJ, Chutkow WA, Yoshioka J, Lee RT. The interaction of thioredoxin with Txnip. Evidence for formation of a mixed disulfide by disulfide exchange. J Biol Chem. 2006;281:21884.
Perry DK, Carton J, Shah AK, Meredith F, Uhlinger DJ, Hannun YA. Serine palmitoyltransferase regulates de novo ceramide generation during etoposide-induced apoptosis. J Biol Chem. 2000;275:9078.
Perry DK. The role of de novo ceramide synthesis in chemotherapy-induced apoptosis. Ann N Y Acad Sci. 2000;905:91.
Perry RJ, Ridgway ND. Molecular mechanisms and regulation of ceramide transport. Biochim Biophys Acta. 2005;1734:220.
Petrache I, Natarajan V, Zhen L, Medler TR, Richter AT, Cho C, Hubbard WC, Berdyshev EV, Tuder RM. Ceramide upregulation causes pulmonary cell apoptosis and emphysema-like disease in mice. Nat Med. 2005;11:491.
Phiel CJ, Willson CA, Lee VM, Klein PS. GSK-3alpharegulates production of Alzheimer’s disease amyloid-betapeptides. Nature. 2003;423:435.
Pilcher HR. The ups and downs of lithium. Nature. 2003;425:118.
Quiroz JA, Gould TD, Manji HK. Molecular effects of lithium. Mol Interv. 2004;4:259.
Ravagnan L, Roumier T, Kroemer G. Mitochondria, the killer organelles and their weapons. J. Cell. Physiol. 2002;192:131.
Read SH, Baliga BC, Ekert PG, Vaux DL, Kumar S. A novel Apaf-1-independent putative caspase-2 activation complex. J Cell Biol. 2002;159:739.
Reed JC. Bcl-2 family proteins. Oncogene. 1998;17:3225.
Robertson JD, Enoksson M, Suomela M, Zhivotovsky B, Orrenius S. Caspase-2 acts upstream of mitochondria to promote cytochrome c release during etoposide-induced apoptosis. J Biol Chem. 2002;277:29803.
Ruvolo PP, Deng X, Ito T, Carr BK, May WS. Ceramide induces Bcl2 dephosphorylation via a mechanism involving mitochondrial PP2A. J Biol Chem. 1999;274:20296.
Ruvolo PP, Deng X, May WS. Phosphorylation of Bcl2 and regulation of apoptosis. Leukemia. 2001;15:515.
Ruvolo PP, Clark W, Mumby M, Gao F, May WS. A functional role for the B56 -subunit of protein phosphatase 2A in ceramide-mediated regulation of Bcl2 phosphorylation status and function. J Biol Chem. 2002;277:22847.
Ruvolo PP. Intracellular signal transduction pathways activated by ceramide and its metabolites. Pharmacol Res. 2003;47:383.
Ryves WJ, Harwood AJ. Lithium inhibits glycogen synthase kinase-3 by competition for magnesium.Biochem Biophys Res Commun. 2001;280:720.
Saitoh M, Nishitoh H, Fujii M, Takeda K, Tobiume K, Sawada Y, Kawabata M, Miyazono K, Ichijo H. Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. EMBO J. 1998;17:2596.
Satoi H, Tomimoto H, Ohtani R, Kitano T, Kondo T, Watanabe M, Oka N, Akiguchi I, Furuya S, Hirabayashi Y, Okazaki T. Astroglial expression of ceramide in Alzheimer's disease brains: a role during neuronal apoptosis. Neuroscience. 2005;130:657.
Sawada M, Nakashima S, Banno Y, Yamakawa H, Hayashi K, Takenaka K, Nishimura Y, Sakai N, Nozawa Y. Ordering of ceramide formation, caspase activation, and Bax/Bcl-2 expression during etoposide-induced apoptosis in C6 glioma cells. Cell Death Differ. 2000;7:761.
Sawai H, Okazaki T, Yamamoto H, Okano H, Takeda Y, Tashima M, Sawada H, Okuma M, Ishikura H, Umehara H. Requirement of AP-1 for ceramide-induced apoptosis in human leukemia HL-60 cells. J Biol Chem. 1995;270:27326.
Sawai H, Domae N, Okazaki T. Current status and perspectives in ceramide-targeting molecular medicine. Curr Pharm Design. 2005;11:2479.
Sayama K, Hanakawa Y, Shirakata Y, Yamasaki K, Sawada Y, Sun L, Yamanishi K, Ichijo H, Hashimoto K. Apoptosis signal-regulating kinase 1 (ASK1) is an intracellular inducer of keratinocyte differentiation. J Biol Chem. 2001;276:999.
Schubert KM, Scheid MP, Duronio V. Ceramide inhibits protein kinase B/Akt by promoting dephosphorylation of serine 473. J Biol Chem. 2000;275:13330.
Schulze PC, Yoshioka J, Takahashi T, He Z, King GL, Lee RT. Hyperglycemia promotes oxidative stress through inhibition of thioredoxin function by thioredoxin-interacting protein. J Biol Chem. 2004;279:30369.
Scorrano L, Oakes SA, Opferman JT, Cheng EH, Sorcinelli MD, Pozzan T, Korsmeyer SJ. BAX and BAK regulation of endoplasmic reticulum Ca2+: a control point for apoptosis. Science. 2003;300:135.
Sheth SS, Bodnar JS, Ghazalpour A, Thipphavong CK, Tsutsumi S, Tward AD, Demant P, Kodama T, Aburatani H, Lusis AJ. Hepatocellular carcinoma in Txnip-deficient mice. Oncogene. 2006;25:3528.
Siskind LJ, Kolesnick RN, Colombini M. Ceramide forms channels in mitochondrial outer membranes at physiologically relevant concentrations. Mitochondrion. 2006;6:118.
Stoica BA, Movsesyan VA, Lea PM 4th, Faden AI. Ceramide-induced neuronal apoptosis is associated with dephosphorylation of Akt, BAD, FKHR, GSK-3, and induction of the mitochondrial-dependent intrinsic caspase pathway. Mol Cell Neurosci. 2003;22:365.
Stoica BA, Movsesyan VA, Knoblach SM, Faden AI. Ceramide induces neuronal apoptosis through mitogen-activated protein kinases and causes release of multiple mitochondrial proteins. Mol Cell Neurosci. 2005;29:355.
Sumitomo M, Ohba M, Asakuma J, Asano T, Asano T, Hayakawa M. Protein kinase Cdelta amplifies ceramide formation via mitochondrial signaling in prostate cancer cells. J Clin Invest. 2002;109:827.
Swanton C, Marani M, Pardo O, Warne PH, Kelly G, Sahai E, Elustondo F, Chang J, Temple J, Ahmed AA, Brenton JD, Downward J, Nicke B. Regulators of mitotic arrest and ceramide metabolism are determinants of sensitivity to paclitaxel and other chemotherapeutic drugs. Cancer Cell. 2007;11:498.
Swanton E, Savory P, Cosulich S, Clarke P, Woodman P. Bcl-2 regulates a caspase-3/caspase-2 apoptotic cascade in cytosolic extracts. Oncogene. 1999;18:1781.
Takahashi Y, Nagata T, Ishii Y, Ikarashi M, Ishikawa K, Asai S. Up-regulation of vitamin D3 up-regulated protein 1 gene in response to 5-fluorouracil in colon carcinoma SW620. Oncol Rep. 2002;9:75.
Takeda K, Matsuzawa A, Nishitoh H, Ichijo H. Roles of MAPKKK ASK1 in stress-induced cell death. Cell Struct Funct. 2003;28:23.
Tanabe H, Eguchi Y, Kamada S, Martinou JC, Tsujimoto Y. Susceptibility of cerebellar granule neurons derived from Bcl-2-deficient and transgenic mice to cell death. Eur J Neurosci. 1997;9:848.
Taniwaki T, Yamada T, Asahara H, Ohyagi Y, Kira J. Ceramide induces apoptosis to immature cerebellar granule cells in culture. Neurochem Res. 1999;24:685.
Tepper AD, de Vries E, van Blitterswijk WJ, Borst J. Ordering of ceramide formation, caspase activation, and mitochondrial changes during CD95- and DNA damage-induced apoptosis. J Clin Invest. 1999;103:971.
Tobiume K, Saitoh M, Ichijo H. Activation of apoptosis signal-regulating kinase 1 by the stress-induced activating phosphorylation of pre-formed oligomer. J Cell Physiol. 2002;191:95.
Tolstykh T, Lee J, Vafai S, Stock JB. Carboxyl methylation regulates phosphoprotein phosphatase 2A by controlling the association of regulatory B subunits. EMBO J. 2000;19:5682.
Tomassini B, Testi R. Mitochondria as sensors of sphingolipids. Biochimie. 2002;84:123.
Troy CM, Shelanski ML. Caspase-2 redux. Cell Death Differ. 2003;10:101.
Tsao CC, Nica AF, Kurinna SM, Jiffar T, Mumby M, Ruvolo PP. Mitochondrial protein phosphatase 2A regulates cell death induced by simulated ischemia in kidney NRK-52E cells. Cell Cycle. 2007;6:2377.
Uchida Y, Itoh M, Taguchi Y, Yamaoka S, Umehara H, Ichikawa S, Hirabayashi Y, Holleran WM, Okazaki T. Ceramide reduction and transcriptional up-regulation of glucosylceramide synthase through doxorubicin-activated Sp1 in drug-resistant HL-60/ADR cells. Cancer Res. 2004;64:6271.
Van Laethem A, Van Kelst S, Lippens S, Declercq W, Vandenabeele P, Janssens S, Vandenheede JR, Garmyn M, Agostinis P. Activation of p38 MAPK is required for Bax translocation to mitochondria, cytochrome c release and apoptosis induced by UVB irradiation in human keratinocytes. FASEB J. 2004;18:1946.
Veis DJ, Sorenson CM, Shutter JR, Korsmeyer SJ. Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell. 1993;75:229.
Vento R, Giuliano M, Lauricella M, Carabillo M, Di Liberto D, Tesoriere G. Induction of programmed cell death in human retinoblastoma Y79 cells by C2-ceramide. Mol Cell Biochem. 1998;185:7.
Vilaboa NE, Galán A, Troyano A, de Blas E, Aller P. Regulation of multidrug resistance 1 (MDR1)/P-glycoprotein gene expression and activity by heat-shock transcription factor 1 (HSF1). J Biol Chem. 2000;275:24970.
von Haefen C, Wieder T, Gillissen B, Starck L, Graupner V, Dorken B, Daniel PT. Ceramide induces mitochondrial activation and apoptosis via a Bax-dependent pathway in human carcinoma cells. Oncogene. 2002;21:4009.
Wallach D, Varfolomeev EE, Malinin NL, Goltsev YV, Kovalenko AV, Boldin MP. Tumor necrosis factor receptor and Fas signaling mechanisms. Annu Rev Immunol. 1999;17:331.
Wang Y, De Keulenaer GW, Lee RT. Vitamin D3-up-regulated protein-1 is a stress-responsive gene that regulates cardiomyocyte viability through interaction with thioredoxin. J Biol Chem. 2002;277:26496.
Willaime S, Vanhoutte P, Caboche J, Lemaigre-Dubreuil Y, Mariani J, Brugg B. Ceramide-induced apoptosis in cortical neurons is mediated by an increase in p38 phosphorylation and not by the decrease in ERK phosphorylation. Eur J Neurosci. 2001;13:2037.
Willaime-Morawek S, Brami-Cherrier K, Mariani J, Caboche J, Brugg B. c-Jun N-terminal kinases/c-Jun and p38 pathways cooperate in ceramide-induced neuronal apoptosis. Neuroscience. 2003;119:387.
Won JS, Singh I. Sphingolipid signaling and redox regulation. Free Radic Biol Med. 2006;40:1875.
Wu D, Marko M, Claycombe K, Paulson K. E, Meydani SN. Ceramide-induced and age-associated increase in macrophage COX-2 expression is mediated through up-regulation of NF-kappa B activity. J Biol Chem. 2003;278:10983.
Xie H, Clarke S. Protein phosphatase 2A is reversibly modified by methyl esterification at its C-terminal leucine residue in bovine brain. J Biol Chem. 1994;269:1981.
Yamawaki H, Haendeler J, Berk BC. Thioredoxin: a key regulator of cardiovascular homeostasis. Circ Res. 2003;93:1029.
Yamawaki H, Pan S, Lee RT, Berk BC. Fluid shear stress inhibits vascular inflammation by decreasing thioredoxin-interacting protein in endothelial cells. J Clin Invest. 2005;115:733.
Yang J, Liu X, Bhalla K, Kim CN, Ibrado AM, Cai J, Peng TI, Jones DP, Wang X. Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science. 1997;275:1129.
Yu XX, Du X, Moreno CS, Green RE, Ogris E, Feng Q, Chou L, McQuoid MJ, Pallas DC. Methylation of the protein phosphatase 2A catalytic subunit is essential for association of B regulatory subunit but not SG2NA, striatin, or polyomavirus middle tumor antigen. Mol Biol Cell. 2001;12:185.
Zhao Y, Boguslawski G, Zitomer RS, DePaoli-Roach AA. Saccharomyces cerevisiae homologs of mammalian B and B' subunits of protein phosphatase 2A direct the enzyme to distinct cellular functions. J Biol Chem. 1997;272:8256.
Zhou G, Mihindukulasuriya KA, MacCorkle-Chosnek RA, Van Hooser A, Hu MC, Brinkley BR, Tan TH. Protein phosphatase 4 is involved in tumor necrosis factor-alpha-induced activation of c-Jun N-terminal kinase. J Biol Chem. 2002;277:6391.
Zimmerman GA, McIntyre TM. PAF, ceramide and pulmonary edema: alveolar flooding and a flood of questions. Trends Mol Med. 2004;10:245.
Zolnierowicz S. Type 2A protein phosphatase, the complex regulator of numerous signaling pathways. Biochem Pharmacol. 2000;60:1225.
Zundel W, Giaccia A. Inhibition of the anti-apoptotic PI(3)K/Akt/Bad pathway by stress. Genes Dev. 1998;12:1941.
論文全文使用權限
  • 同意授權校內瀏覽/列印電子全文服務,於2009-04-02起公開。
  • 同意授權校外瀏覽/列印電子全文服務,於2010-04-02起公開。


  • 如您有疑問,請聯絡圖書館
    聯絡電話:(06)2757575#65773
    聯絡E-mail:etds@email.ncku.edu.tw