Neurochemical Research

, Volume 32, Issue 4–5, pp 577–595 | Cite as

Glycogen Synthase Kinase-3 (GSK3): Inflammation, Diseases, and Therapeutics

  • Richard S. Jope
  • Christopher J. Yuskaitis
  • Eléonore Beurel


Deciphering what governs inflammation and its effects on tissues is vital for understanding many pathologies. The recent discovery that glycogen synthase kinase-3 (GSK3) promotes inflammation reveals a new component of its well-documented actions in several prevalent diseases which involve inflammation, including mood disorders, Alzheimer’s disease, diabetes, and cancer. Involvement in such disparate conditions stems from the widespread influences of GSK3 on many cellular functions, with this review focusing on its regulation of inflammatory processes. GSK3 promotes the production of inflammatory molecules and cell migration, which together make GSK3 a powerful regulator of inflammation, while GSK3 inhibition provides protection from inflammatory conditions in animal models. The involvement of GSK3 and inflammation in these diseases are highlighted. Thus, GSK3 may contribute not only to primary pathologies in these diseases, but also to the associated inflammation, suggesting that GSK3 inhibitors may have multiple effects influencing these conditions.


Glycogen synthase kinase-3 Bipolar disorder Alzheimer’s disease Diabetes Cancer Inflammation Cell migration Lithium 



Research in the authors’ laboratory was supported by grants from the National Institutes of Health.


  1. 1.
    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 107:519–527PubMedCrossRefGoogle Scholar
  2. 2.
    Woodgett JR (1990) Molecular cloning and expression of glycogen synthase kinase-3/factor A. EMBO J 9:2431–2438PubMedGoogle Scholar
  3. 3.
    Jope RS, Johnson GVW (2004) The glamour and gloom of glycogen synthase kinase-3 (GSK3). Trends Biochem Sci 29:95–102PubMedGoogle Scholar
  4. 4.
    Grimes CA, Jope RS (2001) The multi-faceted roles of glycogen synthase kinase-3β in cellular signaling. Prog Neurobiol 65:391–426PubMedGoogle Scholar
  5. 5.
    Bijur GN, Jope RS (2003) Glycogen synthase kinase-3β is highly activated in nuclei and mitochondria. Neuroreport 14:2415–2419PubMedGoogle Scholar
  6. 6.
    Eickholt BJ, Walsh FS, Doherty P (2002) An inactive pool of GSK-3 at the leading edge of growth cones is implicated in Semaphorin 3A signaling. J Cell Biol 157:211–217PubMedGoogle Scholar
  7. 7.
    Trivedi N, Marsh P, Goold RG, Wood-Kaczmar A, Gordon-Weeks PR (2005) Glycogen synthase kinase-3β phosphorylation of MAP1B at Ser1260 and Thr1265 is spatially restricted to growing axons. J Cell Sci 118:993–1005PubMedGoogle Scholar
  8. 8.
    Martin M, Rehani K, Jope RS, Michalek SM (2005) Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3. Nat Immunol 6:777–784PubMedGoogle Scholar
  9. 9.
    Lampson LA (1987) Molecular bases of the immune response to neural antigens. Trends Neurosci 10:211–216Google Scholar
  10. 10.
    Fuchs HE, Bullard DE (1988) Immunology of transplantation in the central nervous system. Appl Neurophysiol 51:278–296PubMedGoogle Scholar
  11. 11.
    Matyszak MK (1998) Inflammation in the CNS: balance between immunological privilege and immune responses. Prog Neurobiol 56:19–35PubMedGoogle Scholar
  12. 12.
    Correale J, Villa A (2004) The neuroprotective role of inflammation in nervous system injuries. J Neurol 251:1304–1316PubMedGoogle Scholar
  13. 13.
    Cartier L, Hartley O, Dubois-Dauphin M, Krause KH (2005) Chemokine receptors in the central nervous system: role in brain inflammation and neurodegenerative diseases. Brain Res Rev 48:16–42PubMedGoogle Scholar
  14. 14.
    Hauwel M, Furon E, Canova C, Griffiths M, Neal J, Gasque P (2005) Innate (inherent) control of brain infection, brain inflammation and brain repair: the role of microglia, astrocytes, “protective” glial stem cells and stromal ependymal cells. Brain Res Rev 48:220–233PubMedGoogle Scholar
  15. 15.
    Kim SU, de Vellis J (2005) Microglia in health and disease. J Neurosci Res 81:302–313PubMedGoogle Scholar
  16. 16.
    Schwartz M, Butovsky O, Bruck W, Hanisch UK (2006) Microglial phenotype: is the commitment reversible? Trends Neurosci 29:68–74PubMedGoogle Scholar
  17. 17.
    Campbell IL (2005) Cytokine-mediated inflammation, tumorigenesis, and disease-associated JAK/STAT/SOCS signaling circuits in the CNS. Brain Res Rev 48:166–177PubMedGoogle Scholar
  18. 18.
    Imitola J, Chitnis T, Khoury SJ (2006) Insights into the molecular pathogenesis of progression in multiple sclerosis: potential implications for future therapies. Arch Neurol 63:25–33PubMedGoogle Scholar
  19. 19.
    Kielian T (2006) Toll-like receptors in central nervous system glial inflammation and homeostasis. J Neurosci Res 83:711–730PubMedGoogle Scholar
  20. 20.
    Hoeflich KP, Luo J, Rubie EA, Tsao M-S, Jin O, Woodgett JR (2000) Requirement for glycogen synthase kinase-3β in cell survival and NF-κB activation. Nature 406:86–90PubMedGoogle Scholar
  21. 21.
    Steinbrecher KA, Wilson W 3rd, Cogswell PC, Baldwin AS (2005) Glycogen synthase kinase 3β functions to specify gene-specific, NF-κB-dependent transcription. Mol Cell Biol 25:8444–8455PubMedGoogle Scholar
  22. 22.
    Dugo L, Collin M, Allen DA, Patel NS, Bauer I, Mervaala EM, Louhelainen M, Foster SJ, Yaqoob MM, Thiemermann C (2005) GSK-3β inhibitors attenuate the organ injury/dysfunction caused by endotoxemia in the rat. Crit Care Med 33:1903–1912PubMedGoogle Scholar
  23. 23.
    Whittle BJ, Varga C, Posa A, Molnar A, Collin M, Thiemermann C (2006) Reduction of experimental colitis in the rat by inhibitors of glycogen synthase kinase-3β. Br J Pharmacol 147:575–582PubMedGoogle Scholar
  24. 24.
    Cuzzocrea S, Mazzon E, Di Paola R, Muia C, Crisafulli C, Dugo L, Collin M, Britti D, Caputi AP, Thiemermann C (2006) Glycogen synthase kinase-3β inhibition attenuates the degree of arthritis caused by type II collagen in the mouse. Clin Immunol 120:57–67PubMedGoogle Scholar
  25. 25.
    Hu X, Paik PK, Chen J, Yarilina A, Kockeritz L, Lu TT, Woodgett JR, Ivashkiv LB (2006) IFN-γ suppresses IL-10 production and synergizes with TLR2 by regulating GSK3 and CREB/AP-1 proteins. Immunity 24:563–574PubMedGoogle Scholar
  26. 26.
    Vicente-Manzanares M, Webb DJ, Horwitz AR (2005) Cell migration at a glance. J Cell Sci 118:4917–4919PubMedGoogle Scholar
  27. 27.
    Etienne-Manneville S, Hall A (2001) Integrin-mediated activation of Cdc42 controls cell polarity in migrating astrocytes through PKCζ. Cell 106:489–498PubMedGoogle Scholar
  28. 28.
    Etienne-Manneville S, Hall A (2003) Cdc42 regulates GSK-3β and adenomatous polyposis coli to control cell polarity. Nature 421:753–756PubMedGoogle Scholar
  29. 29.
    Bazzoni G, Tonetti P, Manzi L, Cera MR, Balconi G, Dejana E (2005) Expression of junctional adhesion molecule-A prevents spontaneous and random motility. J Cell Sci 118:623–632PubMedGoogle Scholar
  30. 30.
    Yoshimura T, Kawano Y, Arimura N, Kawabata S, Kikuchi A, Kaibuchi K (2005) GSK-3β regulates phosphorylation of CRMP-2 and neuronal polarity. Cell 120:137–149PubMedGoogle Scholar
  31. 31.
    Uchida Y, Ohshima T, Sasaki Y, Suzuki H, Yanai S, Yamashita N, Nakamura F, Takei K, Ihara Y, Mikoshiba K, Kolattukudy P, Honnorat J, Goshima Y (2005) Semaphorin3A signalling is mediated via sequential Cdk5 and GSK3β phosphorylation of CRMP2: implication of common phosphorylating mechanism underlying axon guidance and Alzheimer’s disease. Genes Cells 10:165–179PubMedGoogle Scholar
  32. 32.
    Owen R, Gordon-Weeks PR (2003) Inhibition of glycogen synthase kinase 3β in sensory neurons in culture alters filopodia dynamics and microtubule distribution in growth cones. Mol Cell Neurosci 23:626–637PubMedGoogle Scholar
  33. 33.
    Farooqui R, Zhu S, Fenteany G (2006) Glycogen synthase kinase-3 acts upstream of ADP-ribosylation factor 6 and Rac1 to regulate epithelial cell migration. Exp Cell Res 312:1514–1525PubMedGoogle Scholar
  34. 34.
    Koivisto L, Hakkinen L, Matsumoto K, McCulloch CA, Yamada KM, Larjava H (2004) Glycogen synthase kinase-3 regulates cytoskeleton and translocation of Rac1 in long cellular extensions of human keratinocytes. Exp Cell Res 293:68–80PubMedGoogle Scholar
  35. 35.
    Schlaepfer DD, Mitra SK, Ilic D (2004) Control of motile and invasive cell phenotypes by focal adhesion kinase. Biochim Biophys Acta 1692:77–102PubMedGoogle Scholar
  36. 36.
    Bianchi M, De Lucchini S, Marin O, Turner DL, Hanks SK, Villa-Moruzzi E (2005) Regulation of FAK Ser-722 phosphorylation and kinase activity by GSK3 and PP1 during cell spreading and migration. Biochem J 391:359–370PubMedGoogle Scholar
  37. 37.
    Huang D, Cheung AT, Parsons JT, Bryer-Ash M (2002) Focal adhesion kinase (FAK) regulates insulin-stimulated glycogen synthesis in hepatocytes. J Biol Chem 277:18151–18160PubMedGoogle Scholar
  38. 38.
    Cai X, Li M, Vrana J, Schaller MD (2006) Glycogen synthase kinase 3- and extracellular signal-regulated kinase-dependent phosphorylation of paxillin regulates cytoskeletal rearrangement. Mol Cell Biol 26:2857–2868PubMedGoogle Scholar
  39. 39.
    Kobayashi T, Hino S, Oue N, Asahara T, Zollo M, Yasui W, Kikuchi A (2006) Glycogen synthase kinase 3 and h-prune regulate cell migration by modulating focal adhesions. Mol Cell Biol 26:898–911PubMedGoogle Scholar
  40. 40.
    de Melker AA, Desban N, Duband JL (2004) Cellular localization and signaling activity of β-catenin in migrating neural crest cells. Dev Dyn 230:708–726PubMedGoogle Scholar
  41. 41.
    Luo Y, Cai J, Xue H, Mattson MP, Rao MS (2006) SDF1α/CXCR4 signaling stimulates β-catenin transcriptional activity in rat neural progenitors. Neurosci Lett 398:291–295PubMedGoogle Scholar
  42. 42.
    Gates J, Peifer M (2005) Can 1000 reviews be wrong? Actin, α-catenin, and adherens junctions. Cell 123:769–772PubMedGoogle Scholar
  43. 43.
    Bek S, Kemler R (2002) Protein kinase CKII regulates the interaction of β-catenin with α-catenin and its protein stability. J Cell Sci 115:4743–4753PubMedGoogle Scholar
  44. 44.
    Brembeck FH, Schwarz-Romond T, Bakkers J, Wilhelm S, Hammerschmidt M, Birchmeier W (2004) Essential role of BCL9-2 in the switch between β-catenin’s adhesive and transcriptional functions. Genes Dev 18:2225–2230PubMedGoogle Scholar
  45. 45.
    Gottardi CJ, Gumbiner BM (2004) Distinct molecular forms of β-catenin are targeted to adhesive or transcriptional complexes. J Cell Biol 167:339–349PubMedGoogle Scholar
  46. 46.
    Harris TJC, Peifer M (2005) Decisions, decisions: β-catenin chooses between adhesion and transcription. Trends Cell Biol 15:234–237PubMedGoogle Scholar
  47. 47.
    Klein PS, Melton DA (1996) A molecular mechanism for the effect of lithium on development. Proc Natl Acad Sci USA 93:8455–8459PubMedGoogle Scholar
  48. 48.
    Ryves WJ, Harwood AJ (2001) Lithium inhibits glycogen synthase kinase-3 by competition for magnesium. Biochem Biophys Res Commun 280:720–725PubMedGoogle Scholar
  49. 49.
    De Sarno P, Li X, Jope RS (2002) Regulation of Akt and glycogen synthase kinase-3β phosphorylation by sodium valproate and lithium. Neuropharmacology 43:1158–1164PubMedGoogle Scholar
  50. 50.
    Li X, Friedman AB, Zhu W, Wang L, Boswell S, May RS, Davis LL, Jope RS (2006) Lithium regulates glycogen synthase kinase-3β in human peripheral blood mononuclear cells—implications in the treatment of bipolar disorder. Biol Psychiatry (in press)Google Scholar
  51. 51.
    Jope RS (2003) Lithium and GSK3: one inhibitor, two inhibitory actions, multiple outcomes. Trends Pharmacol Sci 24:441–443PubMedGoogle Scholar
  52. 52.
    Zhang F, Phiel CJ, Spece L, Gurvich N, Klein PS (2003) Inhibitory phosphorylation of glycogen synthase kinase-3 (GSK-3) in response to lithium: evidence for autoregulation of GSK-3. J Biol Chem 278:33067–33077PubMedGoogle Scholar
  53. 53.
    Chalecka-Franaszek E, Chuang DM (1999) Lithium activates the serine/threonine kinase Akt-1 and suppresses glutamate-induced inhibition of Akt-1 activity in neurons. Proc Natl Acad Sci USA 96:8745–8750PubMedGoogle Scholar
  54. 54.
    Li X, Zhu W, Roh MS, Friedman AB, Rosborough K, Jope RS (2004) In vivo regulation of glycogen synthase kinase-3β (GSK3β) by serotonergic activity in mouse brain. Neuropsychopharmacology 29:1426–1431PubMedGoogle Scholar
  55. 55.
    Kaidanovich-Beilin O, Milman A, Weizman A, Pick CG, Eldar-Finkelman H (2004) Rapid antidepressive-like activity of specific glycogen synthase kinase-3 inhibitor and its effect on β-catenin in mouse hippocampus. Biol Psychiatry 55:781–784PubMedGoogle Scholar
  56. 56.
    O’Brien WT, Harper AD, Jove F, Woodgett JR, Maretto S, Piccolo S, Klein PS (2004) Glycogen synthase kinase-3β haploinsufficiency mimics the behavioral and molecular effects of lithium. J Neurosci 24:6791–6798PubMedGoogle Scholar
  57. 57.
    Anisman H, Merali Z (2003) Cytokines, stress and depressive illness: brain-immune interactions. Ann Med 35:2–11PubMedGoogle Scholar
  58. 58.
    O’Brien SM, Scott LV, Dinan TG (2004) Cytokines: abnormalities in major depression and implications for pharmacological treatment. Hum Psychopharmacol 19:397–403PubMedGoogle Scholar
  59. 59.
    Schiepers OJG, Wichers MC, Maes M (2005) Cytokines and major depression. Prog Neuropsychopharmacol Biol Psychiatry 29:201–217PubMedGoogle Scholar
  60. 60.
    Licinio J, Wong ML (1999) The role of inflammatory mediators in the biology of major depression: central nervous system cytokines modulate the biological substrate of depressive symptoms, regulate stress-responsive systems, and contribute to neurotoxicity and neuroprotection. Mol Psychiatry 4:317–327PubMedGoogle Scholar
  61. 61.
    Hayley S, Poulter MO, Merali Z, Anisman H (2005) The pathogenesis of clinical depression: stressor- and cytokine-induced alterations of neuroplasticity. Neuroscience 135:659–678PubMedGoogle Scholar
  62. 62.
    Simen BB, Duman CH, Simen AA, Duman RS (2006) TNFα signaling in depression and anxiety: behavioral consequences of individual receptor targeting. Biol Psychiatry 59:775–785PubMedGoogle Scholar
  63. 63.
    Reynolds JL, Ignatowski TA, Sud R, Spengler RN (2005) An antidepressant mechanism of desipramine is to decrease tumor necrosis factor-α production culminating in increases in noradrenergic neurotransmission. Neuroscience 133:519–531PubMedGoogle Scholar
  64. 64.
    Li X, Ketter TA, Frye MA (2002) Synaptic, intracellular, and neuroprotective mechanisms of anticonvulsants: are they relevant for the treatment and course of bipolar disorders? J Affect Disord 69:1–14PubMedGoogle Scholar
  65. 65.
    Peng GS, Li G, Tzeng NS, Chen PS, Chuang DM, Hsu YD, Yang S, Hong JS (2005) Valproate pretreatment protects dopaminergic neurons from LPS-induced neurotoxicity in rat primary midbrain cultures: role of microglia. Mol Brain Res 134:162–169PubMedGoogle Scholar
  66. 66.
    Glauben R, Batra A, Fedke I, Zeitz M, Lehr HA, Leoni F, Mascagni P, Fantuzzi G, Dinarello CA, Siegmund B (2006) Histone hyperacetylation is associated with amelioration of experimental colitis in mice. J Immunol 176:5015–5022PubMedGoogle Scholar
  67. 67.
    Sun X, Sato S, Murayama O, Murayama M, Park JM, Yamaguchi H, Takashima A (2002) Lithium inhibits amyloid secretion in COS7 cells transfected with amyloid precursor protein C100. Neurosci Lett 321:61–64PubMedGoogle Scholar
  68. 68.
    Phiel CJ, Wilson CA, Lee VM, Klein PS (2003) GSK-3α regulates production of Alzheimer’s disease amyloid-β peptides. Nature 423:435–439PubMedGoogle Scholar
  69. 69.
    Li B, Ryder J, Su Y, Zhou Y, Liu F, Ni B (2003) FRAT1 peptide decreases Aβ production in swAPP(751) cells. FEBS Lett 553:347–350PubMedGoogle Scholar
  70. 70.
    Su Y, Ryder J, Li B, Wu X, Fox N, Solenberg P, Brune K, Paul S, Zhou Y, Liu F, Ni B (2004) Lithium, a common drug for bipolar disorder treatment, regulates amyloid-β precursor protein processing. Biochemistry 43:6899–6908PubMedGoogle Scholar
  71. 71.
    Aplin AE, Jacobsen JS, Anderton BH, Gallo JM (1997) Effect of increased glycogen synthase kinase-3 activity upon the maturation of the amyloid precursor protein in transfected cells. Neuroreport 8:639–643PubMedGoogle Scholar
  72. 72.
    Takashima A, Murayama M, Murayama O, Kohno T, Honda T, Yasutake K, Nihonmatsu N, Mercken M, Yamaguchi H, Sugihara S, Wolozin B (1998) Presenilin 1 associates with glycogen synthase kinase-3β and its substrate tau. Proc Natl Acad Sci USA 95:9637–9641PubMedGoogle Scholar
  73. 73.
    Kirschenbaum F, Hsu SC, Cordell B, McCarthy JV (2001) Glycogen synthase kinase-3β regulates presenilin 1 C-terminal fragment levels. J Biol Chem 276:30701–30707PubMedGoogle Scholar
  74. 74.
    Weihl CC, Ghadge GD, Kennedy SG, Hay N, Miller RJ, Roos RP (1999) Mutant presenilin-1 induces apoptosis and downregulates Akt/PKB. J Neurosci 19:5360–5369PubMedGoogle Scholar
  75. 75.
    Zhang Z, Hartmann H, Do VM, Abramowski D, Sturchler-Pierrat C, Staufenbiel M, Sommer B, van de Wetering M, Clevers H, Saftig P, De Strooper B, He X, Yankner BA (1998) Destabilization of β-catenin by mutations in presenilin-1 potentiates neuronal apoptosis. Nature 395:698–702PubMedGoogle Scholar
  76. 76.
    Kim HS, Kim EM, Lee JP, Park CH, Kim S, Seo JH, Chang KA, Yu E, Jeong SJ, Chong YH, Suh YH (2003) C-terminal fragments of amyloid precursor protein exert neurotoxicity by inducing glycogen synthase kinase-3β expression. FASEB J 17:1951–1953PubMedGoogle Scholar
  77. 77.
    Akiyama H, Shin RW, Uchida C, Kitamoto T, Uchida T (2005) Pin1 promotes production of Alzheimer’s amyloid β from β-cleaved amyloid precursor protein. Biochem Biophys Res Commun 336:521–529PubMedGoogle Scholar
  78. 78.
    Ryan KA, Pimplikar SW (2005) Activation of GSK-3 and phosphorylation of CRMP2 in transgenic mice expressing APP intracellular domain. J Cell Biol 171:327–335PubMedGoogle Scholar
  79. 79.
    Takashima A, Noguchi K, Sato K, Hoshino T, Imahori K (1993) Tau protein kinase I is essential for amyloid β-protein-induced neurotoxicity. Proc Natl Acad Sci USA 90:7789–7793PubMedGoogle Scholar
  80. 80.
    Takashima A, Yamaguchi H, Noguchi K, Michel G, Ishiguro K, Sato K, Hoshino T, Hoshi M, Imahori K (1995) Amyloid β peptide induces cytoplasmic accumulation of amyloid protein precursor via tau protein kinase I/glycogen synthase kinase-3β in rat hippocampal neurons. Neurosci Lett 198:83–86PubMedGoogle Scholar
  81. 81.
    Alvarez G, Munoz-Montano JR, Satrustegui J, Avila J, Bogonez E, Diaz-Nido J (1999) Lithium protects cultured neurons against β-amyloid-induced neurodegeneration. FEBS Lett 453:260–264PubMedGoogle Scholar
  82. 82.
    Wei H, Leeds PR, Qian Y, Wei W, Chen R, Chuang D (2000) β-amyloid peptide-induced death of PC 12 cells and cerebellar granule cell neurons is inhibited by long-term lithium treatment. Eur J Pharmacol 392:117–123PubMedGoogle Scholar
  83. 83.
    De Ferrari GV, Chacon MA, Barria MI, Garrido JL, Godoy JA, Olivares G, Reyes AE, Alvarez A, Bronfman M, Inestrosa NC (2003) Activation of Wnt signaling rescues neurodegeneration and behavioral impairments induced by β-amyloid fibrils. Mol Psychiatry 8:195–208PubMedGoogle Scholar
  84. 84.
    Ghribi O, Herman MM, Savory J (2003) Lithium inhibits Aβ-induced stress in endoplasmic reticulum of rabbit hippocampus but does not prevent oxidative damage and tau phosphorylation. J Neurosci Res 71:853–862PubMedGoogle Scholar
  85. 85.
    Fuentealba RA, Farias G, Scheu J, Bronfman M, Marzolo MP, Inestrosa NC (2004) Signal transduction during amyloid-β-peptide neurotoxicity: role in Alzheimer disease. Brain Res Rev 47:275–289PubMedGoogle Scholar
  86. 86.
    Takashima A, Noguchi K, Michel G, Mercken M, Hoshi M, Ishiguro K, Imahori K (1996) Exposure of rat hippocampal neurons to amyloid β peptide (25–35) induces the inactivation of phosphatidylinositol-3 kinase and the activation of tau protein kinase I/glycogen synthase kinase-3β. Neurosci Lett 203:33–36PubMedGoogle Scholar
  87. 87.
    Magrane J, Rosen KM, Smith RC, Walsh K, Gouras GK, Querfurth HW (2005) Intraneuronal β-amyloid expression downregulates the Akt survival pathway and blunts the stress response. J Neurosci 25:10960–10969PubMedGoogle Scholar
  88. 88.
    Ryder J, Su Y, Liu F, Li B, Zhou Y, Ni B (2003) Divergent roles of GSK3 and CDK5 in APP processing. Biochem Biophys Res Commun 312:922–929PubMedGoogle Scholar
  89. 89.
    Johnson GVW, Hartigan JA (1998) Tau protein in normal and Alzheimer’s disease brain: an update. Alzheimer Dis Rev 3:125–141Google Scholar
  90. 90.
    Hanger DP, Hughes K, Woodgett JR, Brion JP, Anderton BH (1992) Glycogen synthase kinase-3 induces Alzheimer’s disease-like phosphorylation of tau: generation of paired helical filament epitopes and neuronal localisation of the kinase. Neurosci Lett 147:58–62PubMedGoogle Scholar
  91. 91.
    Mandelkow EM, Drewes G, Biernat J, Gustke N, Van Lint J, Vandenheede JR, Mandelkow E (1992) Glycogen synthase kinase-3 and the Alzheimer-like state of microtubule-associated protein tau. FEBS Lett 314:315–321PubMedGoogle Scholar
  92. 92.
    Lovestone S, Reynolds CH, Latimer D, Davis DR, Anderton BH, Gallo JM, Hanger D, Mulot S, Marquardt B, Stabel S, Woodgett JR, Miller CCJ (1994) Alzheimer’s disease-like phosphorylation of the microtubule-associated protein tau by glycogen synthase kinase-3 in transfected mammalian cells. Curr Biol 4:1077–1086PubMedGoogle Scholar
  93. 93.
    Hong M, Chen DC, Klein PS, Lee VM (1997) Lithium reduces tau phosphorylation by inhibition of glycogen synthase kinase-3. J Biol Chem 272:25326–25332PubMedGoogle Scholar
  94. 94.
    Cho JH, Johnson GVW (2004) Primed phosphorylation of tau at Thr231 by glycogen synthase kinase 3β (GSK3β) plays a critical role in regulating tau’s ability to bind and stabilize microtubules. J Neurochem 88:349–358PubMedCrossRefGoogle Scholar
  95. 95.
    Hanger DP, Betts JC, Loviny TL, Blackstock WP, Anderton BH (1998) New phosphorylation sites identified in hyperphosphorylated tau (paired helical filament-tau) from Alzheimer’s disease brain using nanoelectrospray mass spectrometry. J Neurochem 71:2465–2476PubMedCrossRefGoogle Scholar
  96. 96.
    Hernandez F, Perez M, Lucas JJ, Mata AM, Bhat R, Avila J (2004) Glycogen synthase kinase-3 plays a crucial role in tau exon 10 splicing and intranuclear distribution of SC35. Implications for Alzheimer’s disease. J Biol Chem 279:3801–3806Google Scholar
  97. 97.
    Fath T, Eidenmuller J, Brandt R (2002) Tau-mediated cytotoxicity in a pseudohyperphosphorylation model of Alzheimer’s disease. J Neurosci 22:9733–9741PubMedGoogle Scholar
  98. 98.
    Noble W, Planel E, Zehr C, Olm V, Meyerson J, Suleman F, Gaynor K, Wang L, LaFrancois J, Feinstein B, Burns M, Krishnamurthy P, Wen Y, Bhat R, Lewis J, Dickson D, Duff K (2005) Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo. Proc Natl Acad Sci USA 102:6990–6995PubMedGoogle Scholar
  99. 99.
    Spittaels K, Van den Haute C, Van Dorpe J, Geerts H, Mercken M, Bruynseels K, Lasrado R, Vandezande K, Laenen I, Boon T, Van Lint J, Vandenheede J, Moechars D, Loos R, Van Leuven F (2000) Glycogen synthase kinase-3β phosphorylates protein tau and rescues the axonopathy in the central nervous system of human four-repeat tau transgenic mice. J Biol Chem 275:41340–41349PubMedGoogle Scholar
  100. 100.
    Lucas JJ, Hernandez F, Gomez-Ramos P, Moran MA, Hen R, Avila J (2001) Decreased nuclear β-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3β conditional transgenic mice. EMBO J 20:27–39PubMedGoogle Scholar
  101. 101.
    Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL, Finch CE, Frautschy S, Griffin WS, Hampel H, Hull M, Landreth G, Lue L, Mrak R, Mackenzie IR, McGeer PL, O’Banion MK, Pachter J, Pasinetti G, Plata-Salaman C, Rogers J, Rydel R, Shen Y, Streit W, Strohmeyer R, Tooyoma I, Van Muiswinkel FL, Veerhuis R, Walker D, Webster S, Wegrzyniak B, Wenk G, Wyss-Coray T (2000) Inflammation and Alzheimer’s disease. Neurobiol Aging 21:383–421PubMedGoogle Scholar
  102. 102.
    Block ML, Hong JS (2005) Microglia and inflammation-mediated neurodegeneration: multiple triggers with a common mechanism. Prog Neurobiol 76:77–98PubMedGoogle Scholar
  103. 103.
    Sastre M, Klockgether T, Heneka MT (2006) Contribution of inflammatory processes to Alzheimer’s disease: molecular mechanisms. Int J Dev Neurosci 24:167–176PubMedGoogle Scholar
  104. 104.
    Benzing WC, Wujek JR, Ward EK, Shaffer D, Ashe KH, Younkin SG, Brunden KR (1999) Evidence for glial-mediated inflammation in aged APP(SW) transgenic mice. Neurobiol Aging 20:581–589PubMedGoogle Scholar
  105. 105.
    Matsuoka Y, Picciano M, Malester B, LaFrancois J, Zehr C, Daeschner JM, Olschowka JA, Fonseca MI, O’Banion MK, Tenner AJ, Lemere CA, Duff K (2001) Inflammatory responses to amyloidosis in a transgenic mouse model of Alzheimer’s disease. Am J Pathol 158:1345–1354PubMedGoogle Scholar
  106. 106.
    Bach JH, Chae HS, Rah JC, Lee MW, Park CH, Choi SH, Choi JK, Lee SH, Kim YS, Kim KY, Lee WB, Suh YH, Kim SS (2001) C-terminal fragment of amyloid precursor protein induces astrocytosis. J Neurochem 78:109–120PubMedGoogle Scholar
  107. 107.
    Combs CK, Karlo JC, Kao SC, Landreth GE (2001) β-Amyloid stimulation of microglia and monocytes results in TNFα-dependent expression of inducible nitric oxide synthase and neuronal apoptosis. J Neurosci 21:1179–1188PubMedGoogle Scholar
  108. 108.
    Ho GJ, Drego R, Hakimian E, Masliah E (2005) Mechanisms of cell signaling and inflammation in Alzheimer’s disease. Curr Drug Targets Inflamm Allergy 4:247–256PubMedGoogle Scholar
  109. 109.
    Nagele RG, D’Andrea MR, Lee H, Venkataraman V, Wang HY (2003) Astrocytes accumulate Aβ42 and give rise to astrocytic amyloid plaques in Alzheimer disease brains. Brain Res 971:197–209PubMedGoogle Scholar
  110. 110.
    Wyss-Coray T, Loike JD, Brionne TC, Lu E, Anankov R, Yan F, Silverstein SC, Husemann J (2003) Adult mouse astrocytes degrade amyloid-β in vitro and in situ. Nat Med 9:453–457PubMedGoogle Scholar
  111. 111.
    Heneka MT, Wiesinger H, Dumitrescu-Ozimek L, Riederer P, Feinstein DL, Klockgether T (2001) Neuronal and glial coexpression of argininosuccinate synthetase and inducible nitric oxide synthase in Alzheimer disease. J Neuropathol Exp Neurol 60:906–916PubMedGoogle Scholar
  112. 112.
    Griffin WS, Sheng JG, Royston MC, Gentleman SM, McKenzie JE, Graham DI, Roberts GW, Mrak RE (1998) Glial–neuronal interactions in Alzheimer’s disease: the potential role of a ‘cytokine cycle’ in disease progression. Brain Pathol 8:65–72PubMedCrossRefGoogle Scholar
  113. 113.
    Qiu WQ, Ye Z, Kholodenko D, Seubert P, Selkoe DJ (1997) Degradation of amyloid β-protein by a metalloprotease secreted by microglia and other neural and non-neural cells. J Biol Chem 272:6641–6646PubMedGoogle Scholar
  114. 114.
    Liu B, Hong JS (2003) Role of microglia in inflammation-mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention. J Pharmacol Exp Ther 304:1–7PubMedGoogle Scholar
  115. 115.
    Bard F, Cannon C, Barbour R, Burke RL, Games D, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Lieberburg I, Motter R, Nguyen M, Soriano F, Vasquez N, Weiss K, Welch B, Seubert P, Schenk D, Yednock T (2000) Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med 6:916–919PubMedGoogle Scholar
  116. 116.
    Gelinas DS, DaSilva K, Fenili D, St. George-Hyslop P, McLaurin J (2004) Immunotherapy for Alzheimer’s disease. Proc Natl Acad Sci USA 101(Suppl. 2):14657–14662PubMedGoogle Scholar
  117. 117.
    McGeer PL, McGeer EG (2006) NSAIDs and Alzheimer disease: epidemiological, animal model and clinical studies. Neurobiol Aging (in press)Google Scholar
  118. 118.
    Etminan M, Gill S, Samii A (2003) Effect of non-steroidal anti-inflammatory drugs on risk of Alzheimer’s disease: systematic review and meta-analysis of observational studies. BMJ 327:128PubMedGoogle Scholar
  119. 119.
    Zimmet P, Alberti KG, Shaw J (2001) Global and societal implications of the diabetes epidemic. Nature 414:782–787PubMedGoogle Scholar
  120. 120.
    Saltiel AR, Kahn CR (2001) Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414:799–806PubMedGoogle Scholar
  121. 121.
    White MF (2003) Insulin signaling in health and disease. Science 302:1710–1711PubMedGoogle Scholar
  122. 122.
    Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA (1995) Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378:785–789PubMedGoogle Scholar
  123. 123.
    Lawlor MA, Alessi DR (2001) PKB/Akt: a key mediator of cell proliferation, survival and insulin responses? J Cell Sci 114:2903–2910PubMedGoogle Scholar
  124. 124.
    Eldar-Finkelman H (2002) Glycogen synthase kinase 3: an emerging therapeutic target. Trends Mol Med 8:126–132PubMedGoogle Scholar
  125. 125.
    Eldar-Finkelman H, Schreyer S, Shinohara M, LeBoeuf R, Krebs E (1999) Increased glycogen synthase kinase-3 activity in diabetes- and obesity-prone C57BL/6J mice. Diabetes 48:1662–1666PubMedGoogle Scholar
  126. 126.
    Semiz S, Orvig C, McNeill J (2002) Effects of diabetes, vanadium, and insulin on glycogen synthase activation in Wistar rats. Mol Cell Biochem 231:23–35PubMedGoogle Scholar
  127. 127.
    Henriksen EJ, Kinnick TR, Teachey MK, O’Keefe MP, Ring D, Johnson KW (2003) Modulation of muscle insulin resistance by selective inhibition of GSK-3 in Zucker diabetic fatty rats. Am J Physiol Endocrinol Metab 284:892–900Google Scholar
  128. 128.
    Nikoulina SE, Ciaraldi TP, Mudaliar S, Mohideen P, Carter L, Henry RR (2000) Potential role of glycogen synthase kinase-3 in skeletal muscle insulin resistance of type 2 diabetes. Diabetes 49:263–271PubMedGoogle Scholar
  129. 129.
    Laviola L, Belsanti G, Davalli AM, Napoli R, Perrini S, Weir GC, Giorgino R, Giorgino F (2001) Effects of streptozotocin diabetes and diabetes treatment by islet transplantation on in vivo insulin signaling in rat heart. Diabetes 50:2709–2720PubMedGoogle Scholar
  130. 130.
    Gispen WH, Biessels GJ (2000) Cognition and synaptic plasticity in diabetes mellitus. Trends Neurosci 23:542–549PubMedGoogle Scholar
  131. 131.
    Planel E, Miyasaka T, Launey T, Chui DH, Tanemura K, Sato S, Murayama O, Ishiguro K, Tatebayashi Y, Takashima A (2004) Alterations in glucose metabolism induce hypothermia leading to tau hyperphosphorylation through differential inhibition of kinase and phosphatase activities: implications for Alzheimer’s disease. J Neurosci 24:2401–2411PubMedGoogle Scholar
  132. 132.
    Schubert M, Gautam D, Surjo D, Ueki K, Stephanie B, Schubert D, Kondo T, Alber J, Galldiks N, Kustermann E, Arndt S, Jacobs AH, Krone W, Kahn CR, Bruning JC (2004) Role for neuronal insulin resistance in neurodegenerative diseases. Proc Natl Acad Sci USA 101:3100–3105PubMedGoogle Scholar
  133. 133.
    Ho L, Qin W, Pompl PN, Xiang Z, Wang J, Zhao Z, Peng Y, Cambareri G, Rocher A, Mobbs CV, Hof PR, Pasinetti GM (2004) Diet-induced insulin resistance promotes amyloidosis in a transgenic mouse model of Alzheimer’s disease. FASEB J 18:902–904PubMedGoogle Scholar
  134. 134.
    Clodfelder-Miller B, De Sarno P, Zmijewska AA, Song L, Jope RS (2005) Physiological and pathological changes in glucose regulate brain Akt and glycogen synthase kinase-3. J Biol Chem 280:39723–39731PubMedGoogle Scholar
  135. 135.
    Schubert M, Brazil DP, Burks DJ, Kushner JA, Ye J, Flint CL, Farhang-Fallah J, Dikkes P, Warot XM, Rio C, Corfas G, White MF (2003) Insulin receptor substrate-2 deficiency impairs brain growth and promotes tau phosphorylation. J Neurosci 23:7084–7092PubMedGoogle Scholar
  136. 136.
    Withers DJ, Gutierrez JS, Towery H, Burks DJ, Ren JM, Previs S, Zhang Y, Bernal D, Pons S, Shulman GI, Bonner-Weir S, White MF (1998) Disruption of IRS-2 causes type 2 diabetes in mice. Nature 391:900–904PubMedGoogle Scholar
  137. 137.
    Plotkin B, Kaidanovich O, Talior I, Eldar-Finkelman H (2003) Insulin mimetic action of synthetic phosphorylated peptide inhibitors of glycogen synthase kinase-3. J Pharmacol Exp Ther 305:974–980PubMedGoogle Scholar
  138. 138.
    Smith SA, Porter LE, Biswas N, Freed MI (2004) Rosiglitazone, but not glyburide, reduces circulating proinsulin and proinsulin:insulin ratio in type 2 diabetes. J Clin Endocrinol Metab 89:6048–6053PubMedGoogle Scholar
  139. 139.
    Yue TL, Bao W, Gu JL, Cui J, Tao L, Ma XL, Ohlstein EH, Jucker BM (2005) Rosiglitazone treatment in Zucker diabetic fatty rats is associated with ameliorated cardiac insulin resistance and protection from ischemia/reperfusion-induced myocardial injury. Diabetes 54:554–562PubMedGoogle Scholar
  140. 140.
    Ring DB, Johnson KW, Henriksen EJ, Nuss JM, Goff D, Kinnick TR, Ma ST, Reeder JW, Samuels I, Slabiak T, Wagman AS, Hammond ME, Harrison SD (2003) Selective glycogen synthase kinase 3 inhibitors potentiate insulin activation of glucose transport and utilization in vitro and in vivo. Diabetes 52:588–595PubMedGoogle Scholar
  141. 141.
    Cline GW, Johnson K, Regittnig W, Perret P, Tozzo E, Xiao L, Damico C (2002) Effects of a novel glycogen synthase kinase-3 inhibitor on insulin-stimulated glucose metabolism in Zucker diabetic fatty (fa/fa) rats. Diabetes 51:2903–2910PubMedGoogle Scholar
  142. 142.
    Pearce NJ, Arch JR, Clapham JC, Coghlan MP, Corcoran SL, Lister CA, Llano A, Moore GB, Murphy GJ, Smith SA, Taylor CM, Yates JW, Morrison AD, Harper AJ, Roxbee-Cox L, Abuin A, Wargent E, Holder JC (2004) Development of glucose intolerance in male transgenic mice overexpressing human glycogen synthase kinase-3β on a muscle-specific promoter. Metabolism 53:1322–1330PubMedGoogle Scholar
  143. 143.
    Hotamisligil GS, Shargill NS, Spiegelman BM (1993) Adipose expression of tumor necrosis factor-α: direct role in obesity-linked insulin resistance. Science 259:87–91PubMedGoogle Scholar
  144. 144.
    Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS (1997) Protection from obesity-induced insulin resistance in mice lacking TNF-α function. Nature 389:610–614PubMedGoogle Scholar
  145. 145.
    Dandona P, Aljada A, Bandyopadhyay A (2004) Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol 25:4–7PubMedGoogle Scholar
  146. 146.
    Wellen KE, Hotamisligil GS (2005) Inflammation, stress, and diabetes. J Clin Invest 115:1111–1119PubMedGoogle Scholar
  147. 147.
    Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM (2001) C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 286:327–334PubMedGoogle Scholar
  148. 148.
    Klover PJ, Zimmers TA, Koniaris LG, Mooney RA (2003) Chronic exposure to interleukin-6 causes hepatic insulin resistance in mice. Diabetes 52:2784–2789PubMedGoogle Scholar
  149. 149.
    Rotter V, Nagaev I, Smith U (2003) Interleukin-6 (IL-6) induces insulin resistance in 3T3-L1 adipocytes and is, like IL-8 and tumor necrosis factor-α, overexpressed in human fat cells from insulin-resistant subjects. J Biol Chem 278:45777–45784PubMedGoogle Scholar
  150. 150.
    Pickup JC (2004) Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes. Diabetes Care 27:813–823PubMedGoogle Scholar
  151. 151.
    Schmidt MI, Duncan BB, Sharrett AR, Lindberg G, Savage PJ, Offenbacher S, Azambuja MI, Tracy RP, Heiss G (1999) Markers of inflammation and prediction of diabetes mellitus in adults (Atherosclerosis Risk in Communities study): a cohort study. Lancet 353:1649–1652PubMedGoogle Scholar
  152. 152.
    Ciani L, Salinas PC (2005) WNTs in the vertebrate nervous system: from patterning to neuronal connectivity. Nat Rev Neurosci 6:351–362PubMedGoogle Scholar
  153. 153.
    Polakis P (1999) The oncogenic activation of β-catenin. Curr Opin Genet Dev 9:15–21PubMedGoogle Scholar
  154. 154.
    Manoukian AS, Woodgett JR (2002) Role of glycogen synthase kinase-3 in cancer: regulation by Wnts and other signaling pathways. Adv Cancer Res 84:203–229PubMedCrossRefGoogle Scholar
  155. 155.
    Samuels Y, Ericson K (2006) Oncogenic PI3K and its role in cancer. Curr Opin Oncol 18:77–82PubMedGoogle Scholar
  156. 156.
    Lustig B, Behrens J (2003) The Wnt signaling pathway and its role in tumor development. J Cancer Res Clin Oncol 129:199–221PubMedGoogle Scholar
  157. 157.
    Boissan M, Beurel E, Wendum D, Rey C, Lecluse Y, Housset C, Lacombe ML, Desbois-Mouthon C (2005) Overexpression of insulin receptor substrate-2 in human and murine hepatocellular carcinoma. Am J Pathol 167:869–877PubMedGoogle Scholar
  158. 158.
    Leis H, Segrelles C, Ruiz S, Santos M, Paramio JM (2002) Expression, localization, and activity of glycogen synthase kinase 3β during mouse skin tumorigenesis. Mol Carcinog 35:180–185PubMedGoogle Scholar
  159. 159.
    Ban KC, Singh H, Krishnan R, Seow HF (2003) GSK-3β phosphorylation and alteration of β-catenin in hepatocellular carcinoma. Cancer Lett 199:201–208PubMedGoogle Scholar
  160. 160.
    Desbois-Mouthon C, Blivet-Van Eggelpoel MJ, Beurel E, Boissan M, Delelo R, Cadoret A, Capeau J (2002) Dysregulation of glycogen synthase kinase-3β signaling in hepatocellular carcinoma cells. Hepatology 36:1528–1536PubMedGoogle Scholar
  161. 161.
    Goto H, Kawano K, Kobayashi I, Sakai H, Yanagisawa S (2002) Expression of cyclin D1 and GSK-3β and their predictive value of prognosis in squamous cell carcinomas of the tongue. Oral Oncol 38:549–556PubMedGoogle Scholar
  162. 162.
    Mulholland DJ, Dedhar S, Wu H, Nelson CC (2006) PTEN and GSK3β: key regulators of progression to androgen-independent prostate cancer. Oncogene 25:329–337PubMedGoogle Scholar
  163. 163.
    Gotoh J, Obata M, Yoshie M, Kasai S, Ogawa K (2003) Cyclin D1 over-expression correlates with β-catenin activation, but not with H-ras mutations, and phosphorylation of Akt, GSK3β and ERK1/2 in mouse hepatic carcinogenesis. Carcinogenesis 24:435–442PubMedGoogle Scholar
  164. 164.
    Shakoori A, Ougolkov A, Yu ZW, Zhang B, Modarressi MH, Billadeau DD, Mai M, Takahashi Y, Minamoto T (2005) Deregulated GSK3β activity in colorectal cancer: its association with tumor cell survival and proliferation. Biochem Biophys Res Commun 334:1365–1373PubMedGoogle Scholar
  165. 165.
    Farago M, Dominguez I, Landesman-Bollag E, Xu X, Rosner A, Cardiff RD, Seldin DC (2005) Kinase-inactive glycogen synthase kinase 3β promotes Wnt signaling and mammary tumorigenesis. Cancer Res 65:5792–5801PubMedGoogle Scholar
  166. 166.
    Fujimuro M, Hayward SD (2004) Manipulation of glycogen-synthase kinase-3 activity in KSHV-associated cancers. J Mol Med 82:223–231PubMedGoogle Scholar
  167. 167.
    Cohen Y, Chetrit A, Cohen Y, Sirota P, Modan B (1998) Cancer morbidity in psychiatric patients: influence of lithium carbonate treatment. Med Oncol 15:32–36PubMedGoogle Scholar
  168. 168.
    Gould TD, Gray NA, Manji HK (2003) Effects of a glycogen synthase kinase-3 inhibitor, lithium, in adenomatous polyposis coli mutant mice. Pharmacol Res 48:49–53PubMedGoogle Scholar
  169. 169.
    Viatour P, Dejardin E, Warnier M, Lair F, Claudio E, Bureau F, Marine JC, Merville MP, Maurer U, Green D, Piette J, Siebenlist U, Bours V, Chariot A (2004) GSK3-mediated BCL-3 phosphorylation modulates its degradation and its oncogenicity. Mol Cell 16:35–45PubMedGoogle Scholar
  170. 170.
    Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M, Hung MC (2004) Dual regulation of Snail by GSK-3β-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol 6:931–940PubMedGoogle Scholar
  171. 171.
    Li J, Mizukami Y, Zhang X, Jo WS, Chung DC (2005) Oncogenic K-ras stimulates Wnt signaling in colon cancer through inhibition of GSK-3β. Gastroenterology 128:1907–1918PubMedGoogle Scholar
  172. 172.
    Welsh GI, Proud CG (1993) Glycogen synthase kinase-3 is rapidly inactivated in response to insulin and phosphorylates eukaryotic initiation factor eIF-2B. Biochem J 294:625–629PubMedGoogle Scholar
  173. 173.
    Pantel K, Brakenhoff RH (2004) Dissecting the metastatic cascade. Nat Rev Cancer 4:448–456PubMedGoogle Scholar
  174. 174.
    Thiery JP (2003) Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol 15:740–746PubMedGoogle Scholar
  175. 175.
    Beurel E, Jope RS (2006) The paradoxical pro- and anti-apoptotic actions of GSK3 in the intrinsic and extrinsic apoptosis signaling pathways. Prog Neurobiol (in press)Google Scholar
  176. 176.
    Watcharasit P, Bijur GN, Zmijewski JW, Song L, Zmijewska A, Chen X, Johnson GVW, Jope RS (2002) Direct, activating interaction between glycogen synthase kinase-3β and p53 after DNA damage. Proc Natl Acad Sci USA 99:7951–7955PubMedGoogle Scholar
  177. 177.
    Beurel E, Kornprobst M, Blivet-Van Eggelpoel MJ, Ruiz-Ruiz C, Cadoret A, Capeau J, Desbois-Mouthon C (2004) GSK3β inhibition by lithium confers resistance to chemotherapy-induced apoptosis through the repression of CD95 (Fas/APO-1) expression. Exp Cell Res 300:354–364PubMedGoogle Scholar
  178. 178.
    Beurel E, Kornprobst M, Blivet-Van Eggelpoel MJ, Cadoret A, Capeau J, Desbois-Mouthon C (2005) GSK-3β reactivation with LY294002 sensitizes hepatoma cells to chemotherapy-induced apoptosis. Int J Oncol 27:215–222PubMedGoogle Scholar
  179. 179.
    Watcharasit P, Bijur GN, Song L, Zhu J, Chen X, Jope RS (2003) Glycogen synthase kinase-3β (GSK3β) binds to and promotes the actions of p53. J Biol Chem 278:48872–48879PubMedGoogle Scholar
  180. 180.
    Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357:539–545PubMedGoogle Scholar
  181. 181.
    Philip M, Rowley DA, Schreiber H (2004) Inflammation as a tumor promoter in cancer induction. Semin Cancer Biol 14:433–439PubMedGoogle Scholar
  182. 182.
    de Visser KE, Eichten A, Coussens LM (2006) Paradoxical roles of the immune system during cancer development. Nat Rev Cancer 6:24–37PubMedGoogle Scholar
  183. 183.
    Coussens LM, Raymond WW, Bergers G, Laig-Webster M, Behrendtsen O, Werb Z, Caughey GH, Hanahan D (1999) Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis. Genes Dev 13:1382–1397PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Richard S. Jope
    • 1
  • Christopher J. Yuskaitis
    • 1
  • Eléonore Beurel
    • 1
  1. 1.Department of Psychiatry and Behavioral NeurobiologyUniversity of Alabama at BirminghamBirminghamUSA

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