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系統識別號 U0026-3006201016071900
論文名稱(中文) 血癌細胞透過肝醣合成酶激酶-3beta增加Galectin-3表現逃脫凋亡刺激
論文名稱(英文) Escape of Leukemia Cells from Apoptotic Stimuli by Glycogen Synthase Kinase-3beta-regulated Galectin-3
校院名稱 成功大學
系所名稱(中) 醫學檢驗生物技術學系碩博士班
系所名稱(英) Department of Medical Laboratory Science and Biotechnology
學年度 98
學期 2
出版年 99
研究生(中文) 鄭怡琳
研究生(英文) Yi-Lin Cheng
學號 t3697409
學位類別 碩士
語文別 英文
論文頁數 76頁
口試委員 指導教授-張權發
共同指導教授-林秋烽
口試委員-林以行
口試委員-陳玉玲
中文關鍵字 Galectin-3  GSK-3β  細胞凋亡  促存活性Bcl-2家族蛋白  血癌 
英文關鍵字 Galectin-3  GSK-3β  apoptosis  pro-survival Bcl-2 family proteins  leukemia 
學科別分類
中文摘要 無論是絲氨酸/酥胺酸激酶之肝醣合成酶激酶-3β (GSK-3β) 或半乳糖苷結合凝集素-3 (Galectin-3),都可以調控癌細胞的生存及凋亡。然而,根據不同的細胞及刺激使得它們會有不同的角色。本研究中我們發現血癌細胞可透過GSK-3β及galectin-3的調控機制而逃脫凋亡刺激。慢性骨髓性血癌細胞株K562在給予順鉑(一種以鉑為基底的化療藥物) (Cisplatin)、神經鞘脂神經醯胺類似物C2-ceramide或磷脂醯肌醇-3激酶(PI3K)抑制劑LY294002的凋亡刺激下,蛋白質分析發現galectin-3會隨著時間透過轉錄作用而增加表現。特別的是galectin-3是在對死亡刺激缺乏感受性的細胞中增加。過量表現galectin-3可幫助細胞抵抗凋亡刺激,然而降低galectin-3表現則增加細胞對凋亡刺激的感受性。誘導表現的galectin-3在細胞中主要分布在粒線體。促存活性Bcl-2家族蛋白的表現(特別是Mcl-1) 在凋亡刺激下會減少,而此現象在過量表現galectin-3後會被抑制,但在減少galectin-3表現後則會增強。在凋亡刺激之下隨著Akt的去活化導致GSK-3β會活化,而在透過藥理的方式及short hairpin RNA方式抑制GSK-3β後則會抑制galectin-3表現並增加凋亡程度以及減少細胞群落的形成,這也代表刺激活化的GSK-3β具有促細胞存活的角色。根據本研究的結果,我們發現GSK-3β會媒介galectin-3的表現進而穩定抗凋亡Bcl-2家族蛋白的表現,而此機制對於血癌細胞逃脫凋亡刺激是非常重要的。以GSK-3β及galectin-3作為標靶治療將可提高現行抗癌藥物如cisplatin的抗血癌效果,以避免抗藥性血癌的發生。
英文摘要 Either serine/threonine kinase glycogen synthase kinas (GSK)-3β or galectin-3, a β-galactoside-binding lectin, is regulated for cancer cell survival and apoptosis depending upon the cell type and stimulus. We investigated a GSK-3β-regulated and galectin-3-mediated mechanism used by leukemia cells to escape from apoptotic stimuli. Galectin-3 expression was time- and transcription-dependently deregulated in K562 chronic myeloid leukemia cells stimulated for apoptosis by cisplatin (a platinum-based chemotherapy drug), sphingolipid ceramide analog C2- ceramide, and LY294002 (a phosphatidylinositol 3-kinase inhibitor). Notably, galectin-3 was upregulated in insusceptible cells, which were resistant to apoptosis. Forced galectin-3 expression caused resistance to apoptosis, whereas knockdown galectin-3 expression increased susceptibility to apoptosis. Sub-cellular distribution of inducible galectin-3 was mitochondria-specific. Apoptotic stimuli decreased pro-survival Bcl-2 family protein expression (especially Mcl-1), whereas galectin-3 overexpression reversed but it was enhanced by a galectin-3 expression knockdown. Under apoptotic stimulation, GSK-3β was activated after Akt was inactivated and GSK-3β was inhibited—either pharmacologically or using short hairpin RNA to abolish galectin-3, increase apoptosis, and inhibit colony formation—which suggests a pro-survival role for GSK-3β. We found that GSK-3β upregulated galectin-3 and stabilized anti-apoptotic Bcl-2 family proteins, which is important for the escape of leukemia cells from apoptotic stimuli. Targeting GSK-3β and galectin-3 enhanced the effect of traditional anticancer drugs, such as cisplatin to prevent development of drug resistance in leukemia.
論文目次 Abstract in Chinese 1
Abstract in English 2
Acknowledgement 3
Abbreviations 4
Contents 7
List of Figures 10
I Introduction 12
I-1 Drug resistance in leukemia 12
I-2 Apoptotic stimuli 12
I-3 Galectins 13
I-4 The role of Galectin-3 in tumorigenesis 14
I-5 The role of Galectin-3 in apoptosis 14
I-6 The role of GSK-3β in apoptosis 15
I-7 The apoptotic role of GSK-3β in leukemia 16
II Study Objective and Specific Aims 18
II-1 Objective 18
II-2 Specific aims 18
II-3 Study Flow Chart 18
III Materials and Methods 20
III-1 Cell cultures and reagents 20
III-2 Western blot analysis 20
III-3 Analyzing cell apoptosis 21
III-4 Immunostaining 22
III-5 Plasmid transfection 22
III-6 Lentiviral-based short hairpin RNA 22
III-7 Colony forming assay 23
III-8 Total RNA extraction and RT-PCR 23
III-9 Statistical analysis 24
IV Results 25
IV-1 Apoptotic stimuli transcription-dependently induce galectin-3 expression in K562 chronic myeloid leukemia cells 25
IV-2 Inducible galectin-3 is important for the survival of apoptotically stimulated cells 25
IV-3 Inducible galectin-3 is highly expressed in apoptotically stimulated mitochondria 26
IV-4 Inducible galectin-3 stabilizes apoptotically stimulated Mcl-1, Bcl-xL, and Bcl-2 26
IV-5 Activation of GSK-3β is essential for inducible galectin-3 expression and survival in apoptotically stimulated cells. 27
IV-6 GSK-3β participates in galectin-3 expression, in part, through transcriptional regulation 28
IV-7 GSK-3β and galectin-3 are critical for the survival of apoptotically stimulated cells 28
V Discussion 30
V-1 The brief summary of the study 30
V-2 The role of inducible galectin-3 in apoptosis 30
V-3 The anti-apoptotic mechanisms of inducible galectin-3 31
V-4 The molecular mechanism of galectin-3 expression regulated by GSK-3β 32
V-5 The relationship between Mcl-1 and GSK-3β 32
VI Conclusion 34
References 35
Figures and Figure Legends 44
Appendix 59
A Materials 59
A-1 Chemicals 59
A-2 Antibodies 61
A-3 Kits 62
A-4 Consumables 62
A-5 Apparatus 62
B Methods 63
B-1 Cell Culture 63
B-1.1 Cell Culture Medium 63
B-1.2 Cell Passage 64
B-1.3 Cell Freeze 64
B-1.4 Cell Defreeze 64
B-2 Western Blot 64
B-2.1 Lysis buffer 64
B-2.2 5× loading dye and TBS-T 65
B-2.3 Running gel preparation 65
B-2.4 Stacking gel preparation 66
B-2.5 Cell lysate preparation 66
B-2.6 SDS-PAGE 66
B-3 Immunocytochemistry 67
B-4 PI staining 67
B-5 RT-PCR 67
B-5.1RNA extraction 67
B-5.2 RT 68
B-5.3 PCR 68
B-6 Lentiviral-based shRNA knockdown 69
B-6.1 Plasmid preparation 69
B-6.2 Lentiviral production 69
B-6.3 Lentiviral concentration 71
B-6.4 Lentiviral infection 71
B-7 Overexpression 72
B-7.1 Cloning 72
B-7.1 Plasmid transfection 73
B-8 Colony forming assay 73

參考文獻 Akahani S, Nangia-Makker P, Inohara H, Kim HR, Raz A (1997). Galectin-3: a novel antiapoptotic molecule with a functional BH1 (NWGR) domain of Bcl-2 family. Cancer Res 57: 5272-6.

Asakuma J, Sumitomo M, Asano T, Hayakawa M (2003). Selective Akt inactivation and tumor necrosis actor-related apoptosis-inducing ligand sensitization of renal cancer cells by low concentrations of paclitaxel. Cancer Res 63: 1365-70.

Barondes SH, Castronovo V, Cooper DN, Cummings RD, Drickamer K, Feizi T et al (1994). Galectins: a family of animal beta-galactoside-binding lectins. Cell 76: 597-8.

Berberat PO, Friess H, Wang L, Zhu Z, Bley T, Frigeri L et al (2001). Comparative analysis of galectins in primary tumors and tumor metastasis in human pancreatic cancer. J Histochem Cytochem 49: 539-49.

Beurel E, Jope RS (2006). The paradoxical pro- and anti-apoptotic actions of GSK3 in the intrinsic and extrinsic apoptosis signaling pathways. Prog Neurobiol 79: 173-89.

Bhat RV, Leonov S, Luthman J, Scott CW, Lee CM (2002). Interactions between GSK3beta and caspase signalling pathways during NGF deprivation induced cell death. J Alzheimers Dis 4: 291-301.

Bijur GN, De Sarno P, Jope RS (2000). Glycogen synthase kinase-3beta facilitates staurosporine- and heat shock-induced apoptosis. Protection by lithium. J Biol Chem 275: 7583-90.

Birbes H, El Bawab S, Obeid LM, Hannun YA (2002). Mitochondria and ceramide: intertwined roles in regulation of apoptosis. Adv Enzyme Regul 42: 113-29.

Califice S, Castronovo V, Bracke M, van den Brule F (2004). Dual activities of galectin-3 in human prostate cancer: tumor suppression of nuclear galectin-3 vs tumor promotion of cytoplasmic galectin-3. Oncogene 23: 7527-36.

Chatterjee M, Wu S (2001). Involvement of Fas receptor and not tumor necrosis factor-alpha receptor in ultraviolet-induced activation of acid sphingomyelinase. Mol Carcinog 30: 47-55.

Cooper DN (2002). Galectinomics: finding themes in complexity. Biochim Biophys Acta 1572: 209-31.

Dancer JY, Truong LD, Zhai Q, Shen SS Expression of Galectin-3 in renal neoplasms: a diagnostic, possible prognostic marker. Arch Pathol Lab Med 134: 90-4.

De Toni F, Racaud-Sultan C, Chicanne G, Mas VM, Cariven C, Mesange F et al (2006). A crosstalk between the Wnt and the adhesion-dependent signaling pathways governs the chemosensitivity of acute myeloid leukemia. Oncogene 25: 3113-22.

Demetriou M, Granovsky M, Quaggin S, Dennis JW (2001). Negative regulation of T-cell activation and autoimmunity by Mgat5 N-glycosylation. Nature 409: 733-9.

Dimanche-Boitrel MT, Meurette O, Rebillard A, Lacour S (2005). Role of early plasma membrane events in chemotherapy-induced cell death. Drug Resist Updat 8: 5-14.

Ding Q, He X, Xia W, Hsu JM, Chen CT, Li LY et al (2007). Myeloid cell leukemia-1 inversely correlates with glycogen synthase kinase-3beta activity and associates with poor prognosis in human breast cancer. Cancer Res 67: 4564-71.

Ding Q, Xia W, Liu JC, Yang JY, Lee DF, Xia J et al (2005). Erk associates with and primes GSK-3beta for its inactivation resulting in upregulation of beta-catenin. Mol Cell 19: 159-70.

Doble BW, Woodgett JR (2003). GSK-3: tricks of the trade for a multi-tasking kinase. J Cell Sci 116: 1175-86.

Dumic J, Dabelic S, Flogel M (2006). Galectin-3: an open-ended story. Biochim Biophys Acta 1760: 616-35.

Dumic J, Lauc G, Flogel M (2000). Expression of galectin-3 in cells exposed to stress-roles of jun and NF-kappaB. Cell Physiol Biochem 10: 149-58.

Elad-Sfadia G, Haklai R, Balan E, Kloog Y (2004). Galectin-3 augments K-Ras activation and triggers a Ras signal that attenuates ERK but not phosphoinositide 3-kinase activity. J Biol Chem 279: 34922-30.

Embi N, Rylatt DB, Cohen P (1980). Glycogen synthase kinase-3 from rabbit skeletal muscle. Separation from cyclic-AMP-dependent protein kinase and phosphorylase kinase. Eur J Biochem 107: 519-27.

Frame S, Cohen P (2001). GSK3 takes centre stage more than 20 years after its discovery. Biochem J 359: 1-16.

Fukumori T, Kanayama HO, Raz A (2007). The role of galectin-3 in cancer drug resistance. Drug Resist Updat 10: 101-8.

Fukumori T, Oka N, Takenaka Y, Nangia-Makker P, Elsamman E, Kasai T et al (2006). Galectin-3 regulates mitochondrial stability and antiapoptotic function in response to anticancer drug in prostate cancer. Cancer Res 66: 3114-9.

Fukumori T, Takenaka Y, Yoshii T, Kim HR, Hogan V, Inohara H et al (2003). CD29 and CD7 mediate galectin-3-induced type II T-cell apoptosis. Cancer Res 63: 8302-11.

Gottesman MM (2002). Mechanisms of cancer drug resistance. Annu Rev Med 53: 615-27.

Grimes CA, Jope RS (2001). The multifaceted roles of glycogen synthase kinase 3beta in cellular signaling. Prog Neurobiol 65: 391-426.

Hannun YA, Luberto C (2000). Ceramide in the eukaryotic stress response. Trends Cell Biol 10: 73-80.

Hannun YA, Obeid LM (1995). Ceramide: an intracellular signal for apoptosis. Trends Biochem Sci 20: 73-7.

Hetman M, Cavanaugh JE, Kimelman D, Xia Z (2000). Role of glycogen synthase kinase-3beta in neuronal apoptosis induced by trophic withdrawal. J Neurosci 20: 2567-74.

Holmes T, O'Brien TA, Knight R, Lindeman R, Symonds G, Dolnikov A (2008). The role of glycogen synthase kinase-3beta in normal haematopoiesis, angiogenesis and leukaemia. Curr Med Chem 15: 1493-9.

Hongisto V, Smeds N, Brecht S, Herdegen T, Courtney MJ, Coffey ET (2003). Lithium blocks the c-Jun stress response and protects neurons via its action on glycogen synthase kinase 3. Mol Cell Biol 23: 6027-36.

Hoyer KK, Pang M, Gui D, Shintaku IP, Kuwabara I, Liu FT et al (2004). An anti-apoptotic role for galectin-3 in diffuse large B-cell lymphomas. Am J Pathol 164: 893-902.

Hsu DK, Dowling CA, Jeng KC, Chen JT, Yang RY, Liu FT (1999). Galectin-3 expression is induced in cirrhotic liver and hepatocellular carcinoma. Int J Cancer 81: 519-26.

Huflejt ME, Turck CW, Lindstedt R, Barondes SH, Leffler H (1993). L-29, a soluble lactose-binding lectin, is phosphorylated on serine 6 and serine 12 in vivo and by casein kinase I. J Biol Chem 268: 26712-8.

Hughes K, Nikolakaki E, Plyte SE, Totty NF, Woodgett JR (1993). Modulation of the glycogen synthase kinase-3 family by tyrosine phosphorylation. EMBO J 12: 803-8.

Jope RS, Johnson GV (2004). The glamour and gloom of glycogen synthase kinase-3. Trends Biochem Sci 29: 95-102.

Kim HR, Lin HM, Biliran H, Raz A (1999). Cell cycle arrest and inhibition of anoikis by galectin-3 in human breast epithelial cells. Cancer Res 59: 4148-54.

Kim K, Mayer EP, Nachtigal M (2003). Galectin-3 expression in macrophages is signaled by Ras/MAP kinase pathway and up-regulated by modified lipoproteins. Biochim Biophys Acta 1641: 13-23.

King TD, Bijur GN, Jope RS (2001). Caspase-3 activation induced by inhibition of mitochondrial complex I is facilitated by glycogen synthase kinase-3beta and attenuated by lithium. Brain Res 919: 106-14.

Kong JY, Klassen SS, Rabkin SW (2005). Ceramide activates a mitochondrial p38 mitogen-activated protein kinase: a potential mechanism for loss of mitochondrial transmembrane potential and apoptosis. Mol Cell Biochem 278: 39-51.

Lacour S, Hammann A, Grazide S, Lagadic-Gossmann D, Athias A, Sergent O et al (2004). Cisplatin-induced CD95 redistribution into membrane lipid rafts of HT29 human colon cancer cells. Cancer Res 64: 3593-8.

Lee YJ, Song YK, Song JJ, Siervo-Sassi RR, Kim HR, Li L et al (2003). Reconstitution of galectin-3 alters glutathione content and potentiates TRAIL-induced cytotoxicity by dephosphorylation of Akt. Exp Cell Res 288: 21-34.

Leffler H, Carlsson S, Hedlund M, Qian Y, Poirier F (2004). Introduction to galectins. Glycoconj J 19: 433-40.

Lin CF, Chen CL, Chang WT, Jan MS, Hsu LJ, Wu RH et al (2005). Bcl-2 rescues ceramide- and etoposide-induced mitochondrial apoptosis through blockage of caspase-2 activation. J Biol Chem 280: 23758-65.

Lin CF, Chen CL, Chang WT, Jan MS, Hsu LJ, Wu RH et al (2004). Sequential caspase-2 and caspase-8 activation upstream of mitochondria during ceramideand etoposide-induced apoptosis. J Biol Chem 279: 40755-61.

Lin CF, Chen CL, Chiang CW, Jan MS, Huang WC, Lin YS (2007). GSK-3beta acts downstream of PP2A and the PI 3-kinase-Akt pathway, and upstream of caspase-2 in ceramide-induced mitochondrial apoptosis. J Cell Sci 120: 2935-43.

Lin CF, Chen CL, Lin YS (2006). Ceramide in apoptotic signaling and anticancer therapy. Curr Med Chem 13: 1609-16.

Lin HM, Pestell RG, Raz A, Kim HR (2002). Galectin-3 enhances cyclin D(1) promoter activity through SP1 and a cAMP-responsive element in human breast epithelial cells. Oncogene 21: 8001-10.

Liu FT, Patterson RJ, Wang JL (2002). Intracellular functions of galectins. Biochim Biophys Acta 1572: 263-73.

Liu FT, Rabinovich GA (2005). Galectins as modulators of tumour progression. Nat Rev Cancer 5: 29-41.

Loberg RD, Vesely E, Brosius FC, 3rd (2002). Enhanced glycogen synthase kinase-3beta activity mediates hypoxia-induced apoptosis of vascular smooth muscle cells and is prevented by glucose transport and metabolism. J Biol Chem 277: 41667-73.

Lotan R, Ito H, Yasui W, Yokozaki H, Lotan D, Tahara E (1994). Expression of a 31-kDa lactoside-binding lectin in normal human gastric mucosa and in primary and metastatic gastric carcinomas. Int J Cancer 56: 474-80.

Lu D, Zhao Y, Tawatao R, Cottam HB, Sen M, Leoni LM et al (2004). Activation of the Wnt signaling pathway in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A 101: 3118-23.

Ma C, Bower KA, Chen G, Shi X, Ke ZJ, Luo J (2008). Interaction between ERK and GSK3beta mediates basic fibroblast growth factor-induced apoptosis in SK-N-MC neuroblastoma cells. J Biol Chem 283: 9248-56.

Maccarrone M, Nieuwenhuizen WE, Dullens HF, Catani MV, Melino G, Veldink GA et al (1996). Membrane modifications in human erythroleukemia K562 cells during induction of programmed cell death by transforming growth factor beta 1 or cisplatin. Eur J Biochem 241: 297-302.

Maguer-Satta V, Burl S, Liu L, Damen J, Chahine H, Krystal G et al (1998). BCR-ABL accelerates C2-ceramide-induced apoptosis. Oncogene 16: 237-48.

Maurer U, Charvet C, Wagman AS, Dejardin E, Green DR (2006). Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1. Mol Cell 21: 749-60.

Mimeault M (2002). New advances on structural and biological functions of ceramide in apoptotic/necrotic cell death and cancer. FEBS Lett 530: 9-16.

Mora A, Sabio G, Risco AM, Cuenda A, Alonso JC, Soler G et al (2002). Lithium blocks the PKB and GSK3 dephosphorylation induced by ceramide through protein phosphatase-2A. Cell Signal 14: 557-62.

Nakahara S, Oka N, Raz A (2005). On the role of galectin-3 in cancer apoptosis. Apoptosis 10: 267-75.

Noda S, Yoshimura S, Sawada M, Naganawa T, Iwama T, Nakashima S et al (2001). Role of ceramide during cisplatin-induced apoptosis in C6 glioma cells. J Neurooncol 52: 11-21.

Ochieng J, Furtak V, Lukyanov P (2004). Extracellular functions of galectin-3. Glycoconj J 19: 527-35.

Ougolkov AV, Bone ND, Fernandez-Zapico ME, Kay NE, Billadeau DD (2007). Inhibition of glycogen synthase kinase-3 activity leads to epigenetic silencing of nuclear factor kappaB target genes and induction of apoptosis in chronic lymphocytic leukemia B cells. Blood 110: 735-42.

Pap M, Cooper GM (1998). Role of glycogen synthase kinase-3 in the phosphatidylinositol 3-Kinase/Akt cell survival pathway. J Biol Chem 273: 19929-32.

Patel S, Woodgett J (2008). Glycogen synthase kinase-3 and cancer: good cop, bad cop? Cancer Cell 14: 351-3.

Pearl LH, Barford D (2002). Regulation of protein kinases in insulin, growth factor and Wnt signalling. Curr Opin Struct Biol 12: 761-7.

Pegram M, Hsu S, Lewis G, Pietras R, Beryt M, Sliwkowski M et al (1999). Inhibitory effects of combinations of HER-2/neu antibody and chemotherapeutic agents used for treatment of human breast cancers. Oncogene 18: 2241-51.

Pettus BJ, Chalfant CE, Hannun YA (2002). Ceramide in apoptosis: an overview and current perspectives. Biochim Biophys Acta 1585: 114-25.

Pettus BJ, Chalfant CE, Hannun YA (2004). Sphingolipids in inflammation: roles and implications. Curr Mol Med 4: 405-18.

Previati M, Lanzoni I, Corbacella E, Magosso S, Guaran V, Martini A et al (2006). Cisplatin-induced apoptosis in human promyelocytic leukemia cells. Int J Mol Med 18: 511-6.

Rossig L, Badorff C, Holzmann Y, Zeiher AM, Dimmeler S (2002). Glycogen synthase kinase-3 couples AKT-dependent signaling to the regulation of p21Cip1 degradation. J Biol Chem 277: 9684-9.

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.

Schoepfer R (1993). The pRSET family of T7 promoter expression vectors for Escherichia coli. Gene 124: 83-5.

Shimura T, Takenaka Y, Fukumori T, Tsutsumi S, Okada K, Hogan V et al (2005). Implication of galectin-3 in Wnt signaling. Cancer Res 65: 3535-7.

Shimura T, Takenaka Y, Tsutsumi S, Hogan V, Kikuchi A, Raz A (2004). Galectin-3, a novel binding partner of beta-catenin. Cancer Res 64: 6363-7.

Siskind LJ, Kolesnick RN, Colombini M (2006). Ceramide forms channels in mitochondrial outer membranes at physiologically relevant concentrations. Mitochondrion 6: 118-25.

Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A et al (2001). Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344: 783-92.

Somervaille TC, Linch DC, Khwaja A (2001). Growth factor withdrawal from primary human erythroid progenitors induces apoptosis through a pathway involving glycogen synthase kinase-3 and Bax. Blood 98: 1374-81.

Song L, De Sarno P, Jope RS (2002). Central role of glycogen synthase kinase-3beta in endoplasmic reticulum stress-induced caspase-3 activation. J Biol Chem 277: 44701-8.

Song S, Mazurek N, Liu C, Sun Y, Ding QQ, Liu K et al (2009). Galectin-3 mediates nuclear beta-catenin accumulation and Wnt signaling in human colon cancer cells by regulation of glycogen synthase kinase-3beta activity. Cancer Res 69: 1343-9.

Stoica BA, Movsesyan VA, Knoblach SM, Faden AI (2005). Ceramide induces neuronal apoptosis through mitogen-activated protein kinases and causes release of multiple mitochondrial proteins. Mol Cell Neurosci 29: 355-71.

Stoica BA, Movsesyan VA, Lea PMt, Faden AI (2003). Ceramide-induced neuronal apoptosis is associated with dephosphorylation of Akt, BAD, FKHR, GSK-3beta, and induction of the mitochondrial-dependent intrinsic caspase pathway. Mol Cell Neurosci 22: 365-82.

Stordal B, Davey M (2007). Understanding cisplatin resistance using cellular models. IUBMB Life 59: 696-9.

Takenaka Y, Fukumori T, Yoshii T, Oka N, Inohara H, Kim HR et al (2004). Nuclear export of phosphorylated galectin-3 regulates its antiapoptotic activity in response to chemotherapeutic drugs. Mol Cell Biol 24: 4395-406.

Tomassini B, Testi R (2002). Mitochondria as sensors of sphingolipids. Biochimie 84: 123-9.

von Haefen C, Wieder T, Gillissen B, Starck L, Graupner V, Dorken B et al (2002). Ceramide induces mitochondrial activation and apoptosis via a Bax-dependent pathway in human carcinoma cells. Oncogene 21: 4009-19.

Wang Q, Zhou Y, Wang X, Evers BM (2006). Glycogen synthase kinase-3 is a negative regulator of extracellular signal-regulated kinase. Oncogene 25: 43-50.

Wang Z, Smith KS, Murphy M, Piloto O, Somervaille TC, Cleary ML (2008). Glycogen synthase kinase 3 in MLL leukaemia maintenance and targeted therapy. Nature 455: 1205-9.

Willaime-Morawek S, Brami-Cherrier K, Mariani J, Caboche J, Brugg B (2003). C-Jun N-terminal kinases/c-Jun and p38 pathways cooperate in ceramide-induced neuronal apoptosis. Neuroscience 119: 387-97.

Willaime S, Vanhoutte P, Caboche J, Lemaigre-Dubreuil Y, Mariani J, Brugg B (2001). 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 13: 2037-46.

Woodgett JR (2001). Judging a protein by more than its name: GSK-3. Sci STKE 2001: re12.

Woodgett JR, Cohen P (1984). Multisite phosphorylation of glycogen synthase. Molecular basis for the substrate specificity of glycogen synthase kinase-3 and casein kinase-II (glycogen synthase kinase-5). Biochim Biophys Acta 788: 339-47.

Xia Y, Wang CZ, Liu J, Anastasio NC, Johnson KM Brain-derived neurotrophic factor prevents phencyclidine-induced apoptosis in developing brain by parallel activation of both the ERK and PI-3K/Akt pathways. Neuropharmacology 58: 330-6.

Xu Q, Simpson SE, Scialla TJ, Bagg A, Carroll M (2003). Survival of acute myeloid leukemia cells requires PI3 kinase activation. Blood 102: 972-80.

Yang RY, Hsu DK, Liu FT (1996). Expression of galectin-3 modulates T-cell growth and apoptosis. Proc Natl Acad Sci U S A 93: 6737-42.

Yang RY, Rabinovich GA, Liu FT (2008). Galectins: structure, function and therapeutic potential. Expert Rev Mol Med 10: e17.

Yin XM, Oltvai ZN, Korsmeyer SJ (1994). BH1 and BH2 domains of Bcl-2 are required for inhibition of apoptosis and heterodimerization with Bax. Nature 369: 321-3.

Yu F, Finley RL, Jr., Raz A, Kim HR (2002). Galectin-3 translocates to the perinuclear membranes and inhibits cytochrome c release from the mitochondria. A role for synexin in galectin-3 translocation. J Biol Chem 277: 15819-27.

Zeng Y, Danielson KG, Albert TJ, Shapiro IM, Risbud MV (2007). HIF-1 alpha is a regulator of galectin-3 expression in the intervertebral disc. J Bone Miner Res 22: 1851-61.

Zhao Y, Altman BJ, Coloff JL, Herman CE, Jacobs SR, Wieman HL et al (2007). Glycogen synthase kinase 3alpha and 3beta mediate a glucose-sensitive antiapoptotic signaling pathway to stabilize Mcl-1. Mol Cell Biol 27: 4328-39.
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