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Regulation of differential pro- and anti-apoptotic signaling by glucocorticoids

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Abstract

More than a quarter of a century ago, the phenomenon of glucocorticoid-induced apoptosis in the majority of hematological cells was first recognized. More recently, glucocorticoid-induced antiapoptotic signaling associated with apoptosis resistance has been identified in cells of epithelial origin, most of malignant solid tumors and some other tissues. Despite these huge amount of data demonstrating differential pro- and anti-apoptotic effects of glucocortioids, the underlying mechanisms of cell type specific glucocorticoid signaling are just beginning to be described. This review summarizes our present understanding of cell type-specific pro- and anti-apoptotic signaling induced by glucocorticoids. In the first section we give a summary and update of known glucocorticoid-induced pathways mediating apoptosis in hematological cells. We shortly introduce mechanisms of glucocorticoid resistance of hematological cells. We highlight and discuss the emerging molecular evidence of a general induction of survival signaling in epithelial cells and carcinoma cells by glucocorticoids. We provide a model for glucocorticoid-induced resistance in cells growing in a tissue formation. Thus, attachment to the extracellular matrix and cell-cell contacts typical for e.g. epithelial and tumor cells may be crucially involved in switching the balance of several interacting pathways to survival upon treatment with glucocorticoids.

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Abbreviations

AP-1:

Activator protein-1

AP-4:

Activator protein-4

ALL:

Acute lymphoblastic leukemia

ASK1/MKKK5:

Apoptosis signal-regulating kinase 1

JNK:

c-Jun NH2-terminal kinases 1, 2,

APO-1/Fas:

CD95

ChIP:

Chromatin immunoprecipitation

CREB:

Cyclic AMP (cAMP)-response element binding protein

DISC:

Death Inducing Signaling Complex

DEX:

Dexamethasone

NO:

Endothelial nitric oxide

ERK:

Extracellular signal-regulated kinase

FOXO1, FOXO3a,:

Forkhead transcription factors

FOXO4:

 

GR:

GC receptor

GCs:

Glucocorticoids

GSK3:

Glycogen synthase kinase 3

H2O2 :

Hydrogen peroxide

IKK:

IκB kinase

IL-6:

Interleukin 6

IGFBP-3:

Insulin growth factor binding protein-3

MEK:

MAPK kinase

MKP-1:

MAP kinase phosphatase-1

(MLK3/MKKK11):

Mixed lineage kinase 3

and (SEK1/MKKK4):

 

NF-κB:

Nuclear factor κB

PI3-K:

Phosphatidylinositol-3 kinase

PDK-1:

Pyruvate dehydrogenase kinase, isoenzyme 1

PARP:

Poly-ADP ribose polymerase

PKC:

Protein kinase C

STK11:

Serine threonine kinase 11

SGK-1:

Serum and glucocorticoid-regulated kinase-1

TDAG8:

T-cell death-associated gene 8

TRAIL:

TNF-related apoptosis-inducing ligand

TNF:

Tumor necrosis factor

References

  1. Rutz HP, Herr I (2004) Interference of glucocorticoids with apoptosis signaling and host-tumor interactions. Cancer Biol Ther 3:715–718

    Article  PubMed  CAS  Google Scholar 

  2. Frei E, Karon M, Levin RH et al (1965) The effectiveness of combinations of antileukemic agents in inducing and maintaining remission in children with acute leukemia. Blood 26:642–656

    PubMed  Google Scholar 

  3. Schmidt S, Rainer J, Ploner C, Presul E, Riml S, Kofler R (2004) Glucocorticoid-induced apoptosis and glucocorticoid resistance: molecular mechanisms and clinical relevance. Cell Death Differ 1(11 Suppl):S45–S55

    Article  CAS  Google Scholar 

  4. Rutz HP (2002) Effects of corticosteroid use on treatment of solid tumours. Lancet 360:1969–1970

    Article  PubMed  CAS  Google Scholar 

  5. Kriegler AB, Bernardo D, Verschoor SM (1994) Protection of murine bone marrow by dexamethasone during cytotoxic chemotherapy. Blood 83:65–71

    PubMed  CAS  Google Scholar 

  6. Weinstein RS, Chen JR, Powers CC et al (2002) Promotion of osteoclast survival and antagonism of bisphosphonate- induced osteoclast apoptosis by glucocorticoids. J Clin Invest 109:1041–1048

    Article  PubMed  CAS  Google Scholar 

  7. Ekert P, MacLusky N, Luo XP et al (1997) Dexamethasone prevents apoptosis in a neonatal rat model of hypoxic-ischemic encephalopathy (HIE) by a reactive oxygen species-independent mechanism. Brain Res 747:9–17

    Article  PubMed  CAS  Google Scholar 

  8. Macaya A, Munell F, Ferrer I, de Torres C, Reventos J (1998) Cell death and associated c-jun induction in perinatal hypoxia- ischemia. Effect of the neuroprotective drug dexamethasone. Brain Res Mol Brain Res 56:29–37

    Article  PubMed  CAS  Google Scholar 

  9. Machein MR, Kullmer J, Ronicke V et al (1999) Differential downregulation of vascular endothelial growth factor by dexamethasone in normoxic and hypoxic rat glioma cells. Neuropathol Appl Neurobiol 25:104–112

    Article  PubMed  CAS  Google Scholar 

  10. Pearl JM, Nelson DP, Schwartz SM et al (2002) Glucocorticoids reduce ischemia-reperfusion-induced myocardial apoptosis in immature hearts. Ann Thorac Surg 74:830–836

    Article  PubMed  Google Scholar 

  11. Zurita M, Vaquero J, Oya S, Morales C (2002) Effects of dexamethasone on apoptosis-related cell death after spinal cord injury. J Neurosurg 96:83–89

    PubMed  CAS  Google Scholar 

  12. Kaufer D, Ogle WO, Pincus ZS et al (2004) Restructuring the neuronal stress response with anti-glucocorticoid gene delivery. Nat Neurosci 7:947–953

    Article  PubMed  CAS  Google Scholar 

  13. Gassler N, Zhang C, Schnabel PA et al (2005) Dexamethasone-induced cisplatin and gemcitabine resistance in lung carcinoma samples treated ex vivo. Brit J Cancer 92:1084–1088

    Article  PubMed  CAS  Google Scholar 

  14. Zhang C, Beckermann B, Kallifatidis G et al (2006) Corticosteroids induce chemotherapy resistance in the majority of tumour cells from bone, brain, breast, cervix, melanoma and neuroblastoma. Int J Oncology (in press).

  15. Zhang C, Kolb A, Buechler P et al (2006) Corticosteroid co-treatment induces resistance to chemotherapy in surgical resections, xenografts and established cell lines of pancreatic cancer. BMC Cancer 6:61

    Article  PubMed  CAS  Google Scholar 

  16. Zhang C, Kolb A, Mattern J et al (2005) Dexamethasone desensitizes hepatocellular and colorectal tumours toward cytotoxic therapy. Cancer Letters (in press).

  17. Zhang C, Marme A, Wenger T et al (2006) Glucocorticoid-mediated inhibition of chemotherapy in ovarian carcinomas. Int J Oncology 2:551–557

    Google Scholar 

  18. Zhang C, Mattern J, Haferkamp A et al (2006) Corticosteroid-induced chemotherapy resistance in urological cancers. Cancer Biol Ther 5:59–64

    Article  PubMed  CAS  Google Scholar 

  19. Mikosz CA, Brickley DR, Sharkey MS, Moran TW, Conzen SD (2001) Glucocorticoid receptor-mediated protection from apoptosis is associated with induction of the serine/threonine survival kinase gene, sgk-1. J Biol Chem 276:16649–16654

    Article  PubMed  CAS  Google Scholar 

  20. Moran TJ, Gray S, Mikosz CA, Conzen SD (2000) The glucocorticoid receptor mediates a survival signal in human mammary epithelial cells. Cancer Res 60:867–872

    PubMed  CAS  Google Scholar 

  21. Pang D, Kocherginsky M, Krausz T, Kim SY, Conzen SD (2006) Dexamethasone decreases xenograft response to paclitaxel through inhibition of tumor cell apoptosis. Cancer Biol Ther (in press).

  22. Sahoo S, Brickley DR, Kocherginsky M, Conzen SD (2005) Coordinate expression of the PI3-kinase downstream effectors serum and glucocorticoid-induced kinase (SGK-1) and Akt-1 in human breast cancer. Eur J Cancer 17:2754–2759

    Article  CAS  Google Scholar 

  23. Wu W, Chaudhuri S, Brickley DR, Pang D, Karrison T, Conzen SD (2004) Microarray analysis reveals glucocorticoid-regulated survival genes that are associated with inhibition of apoptosis in breast epithelial cells. Cancer Res 64:1757–1764

    Article  PubMed  CAS  Google Scholar 

  24. Wu W, Pew T, Zou M, Pang D, Conzen SD (2005) Glucocorticoid receptor-induced MKP-1 expression inhibits paclitaxel-associated MAP kinase activation and contributes to breast cancer cell survival. J Biol Chem 280:4117–4124

    Article  PubMed  CAS  Google Scholar 

  25. Wu W, Zou M, Brickley DR, Pew T, Conzen SD (2006) Glucocorticoid receptor activation signals through FOXO3a in breast cancer cells. Mol Endocrinol

  26. Fan W, Schandl CA, Cheng LR, Norris JS, Willingham MC (1996) Glucocorticoids modulate taxol cytotoxicity in human solid tumor cells. Cell Pharmacol 3:34–348

    Google Scholar 

  27. Sui M, Chen F, Fan W (2006) Glucocorticoids interfere with therapeutic efficacy of paclitaxel against human breast and ovarian xenograft tumors. Int J Cancer 119:712–717

    Article  PubMed  CAS  Google Scholar 

  28. Herr I, Pfitzenmaier J (2006) Glucocorticoid use in prostate cancer and other solid tumors: implications for effectiveness of cytotoxic treatment and metastases. Lancet Oncol 7:425–430

    Article  PubMed  CAS  Google Scholar 

  29. Larue L, Bellacosa A (2005) Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3′ kinase/AKT pathways. Oncogene 24:7443–7454

    Article  PubMed  CAS  Google Scholar 

  30. Letuve S, Druilhe A, Grandsaigne M, Aubier M, Pretolani M (2002) Critical role of mitochondria, but not caspases, during glucocorticosteroid-induced human eosinophil apoptosis. Am J Respir Cell Mol Biol 26:565–571

    PubMed  CAS  Google Scholar 

  31. Buttgereit F, Scheffold A (2002) Rapid glucocorticoid effects on immune cells. Steroids 67:529–534

    Article  PubMed  CAS  Google Scholar 

  32. Limbourg FP, Liao JK (2003) Nontranscriptional actions of the glucocorticoid receptor. J Mol Med 81:168–174

    PubMed  CAS  Google Scholar 

  33. Renner K, Ausserlechner MJ, Kofler R (2003) A conceptual view on glucocorticoid-lnduced apoptosis, cell cycle arrest and glucocorticoid resistance in lymphoblastic leukemia. Curr Mol Med 3:707–717

    Article  PubMed  CAS  Google Scholar 

  34. Tissing WJE, Meijerink JPP, den Boer ML, Pieters R (2003) Molecular determinants of glucocorticoid sensitivity and resistance in acute lymphoblastic leukemia. Leukemia 17:17–25

    Article  PubMed  CAS  Google Scholar 

  35. Schaaf MJ, Cidlowski JA (2002) Molecular mechanisms of glucocorticoid action and resistance. J Steroid Biochem Mol Biol 83:37–48

    Article  PubMed  CAS  Google Scholar 

  36. Greenstein S, Ghias K, Krett NL, Rosen ST (2002) Mechanisms of glucocorticoid-mediated apoptosis in hematological malignancies. Clin Cancer Res 8:1681–1694

    PubMed  CAS  Google Scholar 

  37. Distelhorst CW (2002) Recent insights into the mechanism of glucocorticosteroid-induced apoptosis. Cell Death Differ 9:6–19

    Article  PubMed  CAS  Google Scholar 

  38. Planey SL, Litwack G (2000) Glucocorticoid-induced apoptosis in lymphocytes. Biochem Biophys Res Commun 279:307–312

    Article  PubMed  CAS  Google Scholar 

  39. Kofler R (2000) The molecular basis of glucocorticoid-induced apoptosis of lymphoblastic leukemia cells. Histochem Cell Biol 114:1–7

    PubMed  CAS  Google Scholar 

  40. Brunet CL, Gunby RH, Benson RS, Hickman JA, Watson AJ, Brady G (1998) Commitment to cell death measured by loss of clonogenicity is separable from the appearance of apoptotic markers. Cell Death Differ 5:107–115

    Article  PubMed  CAS  Google Scholar 

  41. Ramdas J, Liu W, Harmon JM (1999) Glucocorticoid-induced cell death requires autoinduction of glucocorticoid receptor expression in human leukemic T cells. Cancer Res 59:1378–1385

    PubMed  CAS  Google Scholar 

  42. Kofler R, Schmidt S, Kofler A, Ausserlechner MJ (2003) Resistance to glucocorticoid-induced apoptosis in lymphoblastic leukemia. J Endocrinol 178:19–27

    Article  PubMed  CAS  Google Scholar 

  43. Cato AC, Nestl A, Mink S (2002) Rapid actions of steroid receptors in cellular signaling pathways. Sci STKE 2002:RE9

    PubMed  Google Scholar 

  44. Ploner C, Schmidt S, Presul E et al (2005) Glucocorticoid-induced apoptosis and glucocorticoid resistance in acute lymphoblastic leukemia. J Steroid Biochem Mol Biol 93:153–160

    Article  PubMed  CAS  Google Scholar 

  45. Sprick MR, Rieser E, Stahl H, Grosse-Wilde A, Weigand MA, Walczak H (2002) Caspase-10 is recruited to and activated at the native TRAIL and CD95 death-inducing signalling complexes in a FADD-dependent manner but can not functionally substitute caspase-8. Embo J 21:4520–4530

    Article  PubMed  CAS  Google Scholar 

  46. Almasan A, Ashkenazi A (2003) Apo2L/TRAIL: apoptosis signaling, biology, and potential for cancer therapy. Cytokine Growth Factor Rev 14:337–348

    Article  PubMed  CAS  Google Scholar 

  47. Green DR, Kroemer G (2004) The pathophysiology of mitochondrial cell death. Science 305:626–629

    Article  PubMed  CAS  Google Scholar 

  48. Herold MJ, McPherson KG, Reichardt HM (2006) Glucocorticoids in T cell apoptosis and function. Cell Mol Life Sci 63:60–72

    Article  PubMed  CAS  Google Scholar 

  49. Strasser A (2005) The role of BH3-only proteins in the immune system. Nat Rev Immunol 5:189–200

    Article  PubMed  CAS  Google Scholar 

  50. Hengartner MO (2000) The biochemistry of apoptosis. Nature 407:770–776

    Article  PubMed  CAS  Google Scholar 

  51. Fulda S, Debatin KM (2006) Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy. Oncogene 25:4798–4811

    Article  PubMed  CAS  Google Scholar 

  52. Cande C, Vahsen N, Kouranti I et al (2004) AIF and cyclophilin A cooperate in apoptosis-associated chromatinolysis. Oncogene 23:1514–1521

    Article  PubMed  CAS  Google Scholar 

  53. Saelens X, Festjens N, Vande Walle L, van Gurp M, van Loo G, Vandenabeele P (2004) Toxic proteins released from mitochondria in cell death. Oncogene 23:2861–2874

    Article  PubMed  CAS  Google Scholar 

  54. Tuckermann JP, Kleiman A, McPherson KG, Reichardt HM (2005) Molecular mechanisms of glucocorticoids in the control of inflammation and lymphocyte apoptosis. Crit Rev Clin Lab Sci 42:71–104

    Article  PubMed  CAS  Google Scholar 

  55. Hakem R, Hakem A, Duncan GS et al (1998) Differential requirement for caspase 9 in apoptotic pathways in vivo. Cell 94:339–352

    Article  PubMed  CAS  Google Scholar 

  56. Kuida K, Haydar TF, Kuan C-Y et al (1998) Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase-9. Cell 94:325–337

    Article  PubMed  CAS  Google Scholar 

  57. Castedo M, Macho A, Zamzami N et al (1995) Mitochondrial perturbations define lymphocytes undergoing apoptotic depletion in vivo. Eur J Immunol 25:3277–3284

    PubMed  CAS  Google Scholar 

  58. Herr I, Ucur E, Herzer K et al (2003) Glucocorticoid co-treatment induces apoptosis resistance toward cancer therapy in carcinomas. Cancer Res 63:3112–3120

    PubMed  CAS  Google Scholar 

  59. Camilleri-Broet S, Vanderwerff H, Caldwell E, Hockenbery D (1998) Distinct alterations in mitochondrial mass and function characterize different models of apoptosis. Exp Cell Res 239:277–292

    Article  PubMed  CAS  Google Scholar 

  60. Wang Z, Malone MH, He H, McColl KS, Distelhorst CW (2003) Microarray analysis uncovers the induction of the proapoptotic BH3-only protein Bim in multiple models of glucocorticoid-induced apoptosis. J Biol Chem 278:23861–23867

    Article  PubMed  CAS  Google Scholar 

  61. Han J, Flemington C, Houghton AB et al (2001) Expression of bbc3, a pro-apoptotic BH3-only gene, is regulated by diverse cell death and survival signals. Proc Natl Acad Sci USA 98:11318–11323

    Article  PubMed  CAS  Google Scholar 

  62. Chauhan D, Auclair D, Robinson EK et al (2002) Identification of genes regulated by dexamethasone in multiple myeloma cells using oligonucleotide arrays. Oncogene 21:1346–1358

    Article  PubMed  CAS  Google Scholar 

  63. Casale F, Addeo R, D’Angelo V et al (2003) Determination of the in vivo effects of prednisone on Bcl-2 family protein expression in childhood acute lymphoblastic leukemia. Int J Oncol 22:123–128

    PubMed  CAS  Google Scholar 

  64. Erlacher M, Michalak EM, Kelly PN et al (2005) BH3-only proteins Puma and Bim are rate-limiting for gamma-radiation- and glucocorticoid-induced apoptosis of lymphoid cells in vivo. Blood 106:4131–4138

    Article  PubMed  CAS  Google Scholar 

  65. Veis DJ, Sorenson CM, Shutter JR, Korsmeyer SJ (1993) Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell 75:229–240

    Article  PubMed  CAS  Google Scholar 

  66. Moutsatsou P, Psarra AM, Tsiapara A, Paraskevakou H, Davaris P, Sekeris CE (2001) Localization of the glucocorticoid receptor in rat brain mitochondria. Arch Biochem Biophys 386:69–78

    Article  PubMed  CAS  Google Scholar 

  67. Scheller K, Seibel P, Sekeris CE (2003) Glucocorticoid and thyroid hormone receptors in mitochondria of animal cells. Int Rev Cytol 222:1–61

    PubMed  Google Scholar 

  68. Scheller K, Sekeris CE, Krohne G, Hock R, Hansen IA, Scheer U (2000) Localization of glucocorticoid hormone receptors in mitochondria of human cells. Eur J Cell Biol 79:299–307

    Article  PubMed  CAS  Google Scholar 

  69. Sionov RV, Cohen O, Kfir S, Zilberman Y, Yefenof E (2006) Role of mitochondrial glucocorticoid receptor in glucocorticoid-induced apoptosis. J Exp Med 203:189–201

    Article  PubMed  CAS  Google Scholar 

  70. Askew DJ, Kuscuoglu U, Brunner T, Green DR, Miesfeld RL (1999) Characterization of Apt- cell lines exhibiting cross-resistance to glucocorticoid- and Fas-mediated apoptosis. Cell Death Differ 6:796–804

    Article  PubMed  CAS  Google Scholar 

  71. Yin XM, Wang K, Gross A et al (1999) Bid-deficient mice are resistant to Fas-induced hepatocellular apoptosis. Nature 400:886–891

    Article  PubMed  CAS  Google Scholar 

  72. Baumann S, Dostert A, Novac N et al (2005) Glucocorticoids inhibit activation-induced cell death (AICD) via direct DNA-dependent repression of the CD95 ligand gene by a glucocorticoid receptor dimer. Blood 106:617–625

    Article  PubMed  CAS  Google Scholar 

  73. Mann CL, Hughes FM Jr, Cidlowski JA (2000) Delineation of the signaling pathways involved in glucocorticoid-induced and spontaneous apoptosis of rat thymocytes. Endocrinology 141:528–538

    Article  PubMed  CAS  Google Scholar 

  74. Sade H, Sarin A (2003) IL-7 inhibits dexamethasone-induced apoptosis via Akt/PKB in mature, peripheral T cells. Eur J Immunol 33:913–919

    Article  PubMed  CAS  Google Scholar 

  75. McColl KS, He H, Zhong H, Whitacre CM, Berger NA, Distelhorst CW (1998) Apoptosis induction by the glucocorticoid hormone dexamethasone and the calcium-ATPase inhibitor thapsigargin involves Bc1-2 regulated caspase activation. Mol Cell Endocrinol 139:229–238

    Article  PubMed  CAS  Google Scholar 

  76. Marchetti MC, Di Marco B, Cifone G, Migliorati G, Riccardi C (2003) Dexamethasone-induced apoptosis of thymocytes: role of glucocorticoid receptor-associated Src kinase and caspase-8 activation. Blood 101:585–593

    Article  PubMed  CAS  Google Scholar 

  77. Salmena L, Lemmers B, Hakem A et al (2003) Essential role for caspase 8 in T-cell homeostasis and T-cell-mediated immunity. Genes Dev 17:883–895

    Article  PubMed  CAS  Google Scholar 

  78. Yoshida H, Kong Y-Y, Yoshida R et al (1998) Apaf1 is required for mitochondrial pathways of apoptosis and brain development. Cell 94:739–750

    Article  PubMed  CAS  Google Scholar 

  79. Lepine S, Lakatos B, Courageot MP, Le Stunff H, Sulpice JC, Giraud F (2004) Sphingosine contributes to glucocorticoid-induced apoptosis of thymocytes independently of the mitochondrial pathway. J Immunol 173:3783–3790

    PubMed  CAS  Google Scholar 

  80. Wang D, Muller N, McPherson KG, Reichardt HM (2006) Glucocorticoids engage different signal transduction pathways to induce apoptosis in thymocytes and mature T cells. J Immunol 176:1695–1702

    PubMed  CAS  Google Scholar 

  81. Nishimura K, Nonomura N, Satoh E et al (2001) Potential mechanism for the effects of dexamethasone on growth of androgen-independent prostate cancer. J Natl Cancer Inst 93:1739–1746

    Article  PubMed  CAS  Google Scholar 

  82. Slee EA, Harte MT, Kluck RM et al (1999) Ordering the cytochrome c-initiated caspase cascade: hierarchical activation of caspases-2, -3, -6, -7, -8, and -10 in a caspase-9-dependent manner. J Cell Biol 144:281–292

    Article  PubMed  CAS  Google Scholar 

  83. Tsujimoto K, Ono T, Sato M, Nishida T, Oguma T, Tadakuma T (2005) Regulation of the expression of caspase-9 by the transcription factor activator protein-4 in glucocorticoid-induced apoptosis. J Biol Chem 280:27638–27644

    Article  PubMed  CAS  Google Scholar 

  84. Ciechanover A (1994) The ubiquitin-proteasome proteolytic pathway. Cell 79:13–21

    Article  PubMed  CAS  Google Scholar 

  85. Beyette J, Mason GG, Murray RZ, Cohen GM, Rivett AJ (1998) Proteasome activities decrease during dexamethasone-induced apoptosis of thymocytes. Biochem J 332(Pt 2):315–320

    PubMed  CAS  Google Scholar 

  86. Hirsch T, Dallaporta B, Zamzami N et al (1998) Proteasome activation occurs at an early, premitochondrial step of thymocyte apoptosis. J Immunol 161:35–40

    PubMed  CAS  Google Scholar 

  87. Grimm LM, Goldberg AL, Poirier GG, Schwartz LM, Osborne BA (1996) Proteasomes play an essential role in thymocyte apoptosis. Embo J 15:3835–3844

    PubMed  CAS  Google Scholar 

  88. Vugmeyster Y, Borodovsky A, Maurice MM, Maehr R, Furman MH, Ploegh HL (2002) The ubiquitin-proteasome pathway in thymocyte apoptosis: caspase-dependent processing of the deubiquitinating enzyme USP7 (HAUSP). Mol Immunol 39:431–441

    Article  PubMed  CAS  Google Scholar 

  89. Dallaporta B, Pablo M, Maisse C et al (2000) Proteasome activation as a critical event of thymocyte apoptosis. Cell Death Differ 7:368–373

    Article  PubMed  CAS  Google Scholar 

  90. Ivanov VN, Nikolic-Zugic J (1998) Biochemical and kinetic characterization of the glucocorticoid-induced apoptosis of immature CD4+CD8+ thymocytes. Int Immunol 10:1807–1817

    Article  PubMed  CAS  Google Scholar 

  91. Frankfurt O, Rosen ST (2004) Mechanisms of glucocorticoid-induced apoptosis in hematologic malignancies: updates. Curr Opin Oncol 16:553–563

    Article  PubMed  CAS  Google Scholar 

  92. Yang Y, Fang S, Jensen JP, Weissman AM, Ashwell JD (2000) Ubiquitin protein ligase activity of IAPs and their degradation in proteasomes in response to apoptotic stimuli. Science 288:874–877

    Article  PubMed  CAS  Google Scholar 

  93. He H, Qi XM, Grossmann J, Distelhorst CW (1998) c-Fos degradation by the proteasome. An early, Bcl-2-regulated step in apoptosis. J Biol Chem 273:25015–25019

    Article  PubMed  CAS  Google Scholar 

  94. Kroemer G, Jaattela M (2005) Lysosomes and autophagy in cell death control. Nat Rev Cancer 5:886–897

    Article  PubMed  CAS  Google Scholar 

  95. Guicciardi ME, Deussing J, Miyoshi H et al (2000) Cathepsin B contributes to TNF-alpha-mediated hepatocyte apoptosis by promoting mitochondrial release of cytochrome c. J Clin Invest 106:1127–1137

    PubMed  CAS  Google Scholar 

  96. Vancompernolle K, Van Herreweghe F, Pynaert G et al (1998) Atractyloside-induced release of cathepsin B, a protease with caspase-processing activity. FEBS Lett 438:150–158

    Article  PubMed  CAS  Google Scholar 

  97. Schotte P, Van Criekinge W, Van de Craen M et al (1998) Cathepsin B-mediated activation of the proinflammatory caspase-11. Biochem Biophys Res Commun 251:379–387

    Article  PubMed  CAS  Google Scholar 

  98. Foghsgaard L, Wissing D, Mauch D et al (2001) Cathepsin B acts as a dominant execution protease in tumor cell apoptosis induced by tumor necrosis factor. J Cell Biol 153:999–1010

    Article  PubMed  CAS  Google Scholar 

  99. Schmidt S, Rainer J, Riml S et al (2006) Identification of glucocorticoid-response genes in children with acute lymphoblastic leukemia. Blood 107:2061–2069

    Article  PubMed  CAS  Google Scholar 

  100. Tonko M, Ausserlechner MJ, Bernhard D, Helmberg A, Kofler R (2001) Gene expression profiles of proliferating vs. G1/G0 arrested human leukemia cells suggest a mechanism for glucocorticoid-induced apoptosis. FASEB J 15:693–699

    Article  PubMed  CAS  Google Scholar 

  101. Planey SL, Abrams MT, Robertson NM, Litwack G (2003) Role of apical caspases and glucocorticoid-regulated genes in glucocorticoid-induced apoptosis of pre-B leukemic cells. Cancer Res 63:172–178

    PubMed  CAS  Google Scholar 

  102. Ishizuka T, Sakata N, Johnson GL, Gelfand EW, Terada N (1997) Rapamycin potentiates dexamethasone-induced apoptosis and inhibits JNK activity in lymphoblastoid cells. Biochem Biophys Res Commun 230:386–391

    Article  PubMed  CAS  Google Scholar 

  103. Yamada M, Hirasawa A, Shiojima S, Tsujimoto G (2003) Granzyme A mediates glucocorticoid-induced apoptosis in leukemia cells. Faseb J 17:1712–1714

    Article  PubMed  CAS  Google Scholar 

  104. Malone MH, Wang Z, Distelhorst CW (2004) The glucocorticoid-induced gene tdag8 encodes a pro-apoptotic G protein-coupled receptor whose activation promotes glucocorticoid-induced apoptosis. J Biol Chem 279:52850–52859

    Article  PubMed  CAS  Google Scholar 

  105. Radu CG, Cheng D, Nijagal A et al (2006) Normal immune development and glucocorticoid-induced thymocyte apoptosis in mice deficient for the T-cell death-associated gene 8 receptor. Mol Cell Biol 26:668–677

    Article  PubMed  CAS  Google Scholar 

  106. Hazlehurst LA, Landowski TH, Dalton WS (2003) Role of the tumor microenvironment in mediating de novo resistance to drugs and physiological mediators of cell death. Oncogene 22:7396–7402

    Article  PubMed  CAS  Google Scholar 

  107. Sionov RV, Kfir S, Zafrir E, Cohen O, Zilberman Y, Yefenof E (2006) Glucocorticoid-induced apoptosis revisited: a novel role for glucocorticoid receptor translocation to the mitochondria. Cell Cycle 5:1017–1026

    PubMed  CAS  Google Scholar 

  108. Tsitoura DC, Rothman PB (2004) Enhancement of MEK/ERK signaling promotes glucocorticoid resistance in CD4+ T cells. J Clin Invest 113:619–627

    Article  PubMed  CAS  Google Scholar 

  109. Grandage VL, Gale RE, Linch DC, Khwaja A (2005) PI3-kinase/Akt is constitutively active in primary acute myeloid leukaemia cells and regulates survival and chemoresistance via NF-kappaB, Mapkinase and p53 pathways. Leukemia 19:586–594

    PubMed  CAS  Google Scholar 

  110. Platanias LC (2003) Map kinase signaling pathways and hematologic malignancies. Blood 101:4667–4679

    Article  PubMed  CAS  Google Scholar 

  111. Chalandon Y, Schwaller J (2005) Targeting mutated protein tyrosine kinases and their signaling pathways in hematologic malignancies. Haematologica 90:949–968

    PubMed  CAS  Google Scholar 

  112. Nuutinen U, Postila V, Matto M et al (2006) Inhibition of PI3-kinase-Akt pathway enhances dexamethasone-induced apoptosis in a human follicular lymphoma cell line. Exp Cell Res 312:322–330

    PubMed  CAS  Google Scholar 

  113. Haarman EG, Kaspers GJ, Veerman AJ (2003) Glucocorticoid resistance in childhood leukaemia: mechanisms and modulation. Br J Haematol 120:919–929

    Article  PubMed  CAS  Google Scholar 

  114. Zhou J, Cidlowski JA (2005) The human glucocorticoid receptor: one gene, multiple proteins and diverse responses. Steroids 70:407–417

    Article  PubMed  CAS  Google Scholar 

  115. Amsterdam A, Sasson R (2002) The anti-inflammatory action of glucocorticoids is mediated by cell type specific regulation of apoptosis. Mol Cell Endocrinol 189:1–9

    Article  PubMed  CAS  Google Scholar 

  116. Messmer UK, Pereda-Fernandez C, Manderscheid M, Pfeilschifter J (2001) Dexamethasone inhibits TNF-alpha-induced apoptosis and IAP protein downregulation in MCF-7 cells. Br J Pharmacol 133:467–476

    Article  PubMed  CAS  Google Scholar 

  117. Buchmann A, Willy C, Buenemann CL, Stroh C, Schmiechen A, Schwarz M (1999) Inhibition of transforming growth factor beta1-induced hepatoma cell apoptosis by liver tumor promoters: characterization of primary signaling events and effects on CPP32-like caspase activity. Cell Death Differ 6:190–200

    Article  PubMed  CAS  Google Scholar 

  118. Yamamoto M, Fukuda K, Miura N, Suzuki R, Kido T, Komatsu Y (1998) Inhibition by dexamethasone of transforming growth factor beta1-induced apoptosis in rat hepatoma cells: a possible association with Bcl-xL induction. Hepatology 27:959–966

    Article  PubMed  CAS  Google Scholar 

  119. Gascoyne DM, Kypta RM, Vivanco Md (2003) Glucocorticoids inhibit apoptosis during fibrosarcoma developmentby transcriptionally activating Bcl-xL. JBC MS301812200

  120. Hammer S, Sauer B, Spika I, Schraut C, Kleuser B, Schafer-Korting M (2004) Glucocorticoids mediate differential anti-apoptotic effects in human fibroblasts and keratinocytes via sphingosine-1-phosphate formation. J Cell Biochem 91:840–851

    Article  PubMed  CAS  Google Scholar 

  121. Cui H, Sherr DH, El-Khatib M et al (1996) Regulation of T-cell death genes: selective inhibition of FasL- but not Fas-mediated function. Cell Immunol 167:276–284

    Article  PubMed  CAS  Google Scholar 

  122. D’Adamio F, Zollo O, Moraca R et al (1997) A new dexamethasone-induced gene of the leucine zipper family protects T lymphocytes from TCR/CD3-activated cell death. Immunity 7:803–812

    Article  PubMed  CAS  Google Scholar 

  123. Iseki R, Mukai M, Iwata M (1991) Regulation of T lymphocyte apoptosis. Signals for the antagonism between activation- and glucocorticoid-induced death. J Immunol 147:4286–4292

    PubMed  CAS  Google Scholar 

  124. Wang R, Zhang L, Zhang X et al (2001) Differential regulation of the expression of CD95 ligand, receptor activator of nuclear factor-kappa B ligand (RANKL), TNF-related apoptosis-inducing ligand (TRAIL), and TNF-alpha during T cell activation. J Immunol 166:1983–1990

    PubMed  CAS  Google Scholar 

  125. Webster JC, Huber RM, Hanson RL et al (2002) Dexamethasone and tumor necrosis factor-alpha act together to induce the cellular inhibitor of apoptosis-2 gene and prevent apoptosis in a variety of cell types. Endocrinology 143:3866–3874

    Article  PubMed  CAS  Google Scholar 

  126. Yang Y, Mercep M, Ware CF, Ashwell JD (1995) Fas and activation-induced Fas ligand mediate apoptosis of T cell hybridomas: inhibition of Fas ligand expression by retinoic acid and glucocorticoids. J Exp Med 181:1673–1682

    Article  PubMed  CAS  Google Scholar 

  127. Yerramasetti R, Gollapudi S, Gupta S (2002) Rifampicin inhibits CD95-mediated apoptosis of Jurkat T cells via glucocorticoid receptors by modifying the expression of molecules regulating apoptosis. J Clin Immunol 22:37–47

    Article  PubMed  CAS  Google Scholar 

  128. Zipp F, Wendling U, Beyer M et al (2000) Dual effect of glucocorticoids on apoptosis of human autoreactive and foreign antigen-specific T cells. J Neuroimmunol 110:214–222

    Article  PubMed  CAS  Google Scholar 

  129. Topper YJ, Freeman CS (1980) Multiple hormone interactions in the developmental biology of the mammary gland. Physiol Rev 60:1049–1106

    PubMed  CAS  Google Scholar 

  130. Feng Z, Marti A, Jehn B, Altermatt HJ, Chicaiza G, Jaggi R (1995) Glucocorticoid and progesterone inhibit involution and programmed cell death in the mouse mammary gland. J Cell Biol 131:1095–1103

    Article  PubMed  CAS  Google Scholar 

  131. Lund LR, Romer J, Thomasset N et al (1996) Two distinct phases of apoptosis in mammary gland involution: proteinase-independent and -dependent pathways. Development 122:181–193

    PubMed  CAS  Google Scholar 

  132. Meyer S, Eden T, Kalirai H (2006) Dexamethasone protects against cisplatin-induced activation of the mitochondrial apoptotic pathway in human osteosarcoma cells. Cancer Biol Ther 5

  133. Rieger J, Durka S, Streffer J, Dichgans J, Weller M (1999) Gemcitabine cytotoxicity of human malignant glioma cells: modulation by antioxidants, BCL-2 and dexamethasone. Eur J Pharmacol 365:301–308

    Article  PubMed  CAS  Google Scholar 

  134. Gorman AM, Hirt UA, Orrenius S, Ceccatelli S (2000) Dexamethasone pre-treatment interferes with apoptotic death in glioma cells. Neuroscience 96:417–425

    Article  PubMed  CAS  Google Scholar 

  135. Wolff JE, Denecke J, Jurgens H (1996) Dexamethasone induces partial resistance to cisplatinum in C6 glioma cells. Anticancer Res 16:805–809

    PubMed  CAS  Google Scholar 

  136. Wolff JE, Jurgens H (1994) Dexamethasone induced partial resistance to methotrexate in C6-glioma cells. Anticancer Res 14:1585–1588

    PubMed  CAS  Google Scholar 

  137. Benedetti S, Pirola B, Poliani PL et al (2003) Dexamethasone inhibits the anti-tumor effect of interleukin 4 on rat experimental gliomas. Gene Ther 10:188–192

    Article  PubMed  CAS  Google Scholar 

  138. Rutz HP, Mariotta M, von Knebel Doeberitz M, Mirimanoff RO (1998) Dexamethasone-induced radioresistance occurring independent of human papilloma virus gene expression in cervical carcinoma cells. Strahlenther Onkol 174:71–74

    Article  PubMed  CAS  Google Scholar 

  139. Kamradt MC, Mohideen N, Krueger E, Walter S, Vaughan AT (2000) Inhibition of radiation-induced apoptosis by dexamethasone in cervical carcinoma cell lines depends upon increased HPV E6/E7. Br J Cancer 82:1709–1716

    Article  PubMed  CAS  Google Scholar 

  140. Kamradt MC, Walter S, Koudelik J et al (2001) Steroid-mediated inhibition of radiation-induced apoptosis in C4-1 cervical carcinoma cells is p53-dependent. Eur J Cancer 37:2240–2246

    Article  PubMed  CAS  Google Scholar 

  141. Evans-Storms RB, Cidlowski JA (2000) Delineation of an antiapoptotic action of glucocorticoids in hepatoma cells: the role of nuclear factor-kappaB. Endocrinology 141:1854–1862

    Article  PubMed  CAS  Google Scholar 

  142. Wen LP, Madani K, Fahrni JA, Duncan SR, Rosen GD (1997) Dexamethasone inhibits lung epithelial cell apoptosis induced by IFN- gamma and Fas. Am J Physiol 273:L921–929

    PubMed  CAS  Google Scholar 

  143. Bergman AM, Pinedo HM, Peters GJ (2001) Steroids affect collateral sensitivity to gemcitabine of multidrug-resistant human lung cancer cells. Eur J Pharmacol 416:19–24

    Article  PubMed  CAS  Google Scholar 

  144. Sengupta S, Vonesch JL, Waltzinger C, Zheng H, Wasylyk B (2000) Negative cross-talk between p53 and the glucocorticoid receptor and its role in neuroblastoma cells. EMBO J 19:6051–6064

    Article  PubMed  CAS  Google Scholar 

  145. Kruit A, Reyes-Moreno C, Newling DW, Geldof A, Koutsilieris M (1999) Response of PC-3 prostate cancer cells to combination therapy using irradiation with glucocorticoids or doxorubicin. Anticancer Res 19:3153–3156

    PubMed  CAS  Google Scholar 

  146. Oh HY, Namkoong S, Lee SJ et al (2006) Dexamethasone protects primary cultured hepatocytes from death receptor-mediated apoptosis by upregulation of cFLIP. Cell Death Differ 13:512–523

    Article  PubMed  CAS  Google Scholar 

  147. Sasson R, Tajima K, Amsterdam A (2001) Glucocorticoids protect against apoptosis induced by serum deprivation, cyclic adenosine 3′,5′-monophosphate and p53 activation in immortalized human granulosa cells: involvement of Bcl-2. Endocrinology 142:802–811

    Article  PubMed  CAS  Google Scholar 

  148. Sasson R, Amsterdam A (2003) Pleiotropic anti-apoptotic activity of glucocorticoids in ovarian follicular cells. Biochem Pharmacol 66:1393–1401

    Article  PubMed  CAS  Google Scholar 

  149. Das A, Banik NL, Patel SJ, Ray SK (2004) Dexamethasone protected human glioblastoma U87MG cells from temozolomide induced apoptosis by maintaining Bax:Bcl-2 ratio and preventing proteolytic activities. Mol Cancer 3:36

    Article  PubMed  CAS  Google Scholar 

  150. Runnebaum IB, Bruning A (2005) Glucocorticoids inhibit cell death in ovarian cancer and up-regulate caspase inhibitor cIAP2. Clin Cancer Res 11:6325–6332

    Article  PubMed  CAS  Google Scholar 

  151. Bailly-Maitre B, de Sousa G, Boulukos K, Gugenheim J, Rahmani R (2001) Dexamethasone inhibits spontaneous apoptosis in primary cultures of human and rat hepatocytes via Bcl-2 and Bcl-xL induction. Cell Death Differ 8:279–288

    Article  PubMed  CAS  Google Scholar 

  152. Messmer UK, Winkel G, Briner VA, Pfeilschifter J (1999) Glucocorticoids potently block tumour necrosis factor-alpha- and lipopolysaccharide-induced apoptotic cell death in bovine glomerular endothelial cells upstream of caspase 3 activation. Br J Pharmacol 127:1633–1640

    Article  PubMed  CAS  Google Scholar 

  153. Beato M, Herrlich P, Schutz G (1995) Steroid hormone receptors: many actors in search of a plot. Cell 83:851–857

    Article  PubMed  CAS  Google Scholar 

  154. Herrlich P (2001) Cross-talk between glucocorticoid receptor and AP-1. Oncogene 20:2465–2475

    Article  PubMed  CAS  Google Scholar 

  155. Novac N, Baus D, Dostert A, Heinzel T (2006) Competition between glucocorticoid receptor and NFkappaB for control of the human FasL promoter. Faseb J 20:1074–1081

    Article  PubMed  CAS  Google Scholar 

  156. Harmon JM, Thompson EB (1981) Isolation and characterization of dexamethasone-resistant mutants from human lymphoid cell line CEM-C7. Mol Cell Biol 1:512–521

    PubMed  CAS  Google Scholar 

  157. Ray A, Prefontaine KE (1994) Physical association and functional antagonism between the p65 subunit of transcription factor NF-kB and the glucocorticoid receptor. Proc Natl Acad Sci USA 91:752–756

    Article  PubMed  CAS  Google Scholar 

  158. Reichardt HM, Kaestner KH, Tuckermann J et al (1998) DNA binding of the glucocorticoid receptor is not essential for survival. Cell 93:531–541

    Article  PubMed  CAS  Google Scholar 

  159. Teicher BA, Herman TS, Holden SA et al (1990) Tumor resistance to alkylating agents conferred by mechanisms operative only in vivo. Science 247:1457–1461

    Article  PubMed  CAS  Google Scholar 

  160. Rennebeck G, Martelli M, Kyprianou N (2005) Anoikis and survival connections in the tumor microenvironment: is there a role in prostate cancer metastasis? Cancer Res 65:11230–11235

    Article  PubMed  CAS  Google Scholar 

  161. Murakami N, Fukuchi S, Takeuchi K, Hori T, Shibamoto S, Ito F (1998) Antagonistic regulation of cell migration by epidermal growth factor and glucocorticoid in human gastric carcinoma cells. J Cell Physiol 176:127–137

    Article  PubMed  CAS  Google Scholar 

  162. Stevenson BR, Siliciano JD, Mooseker MS, Goodenough DA (1986) Identification of ZO-1: a high molecular weight polypeptide associated with the tight junction (zonula occludens) in a variety of epithelia. J Cell Biol 103:755–766

    Article  PubMed  CAS  Google Scholar 

  163. Woo PL, Cha HH, Singer KL, Firestone GL (1996) Antagonistic regulation of tight junction dynamics by glucocorticoids and transforming growth factor-beta in mouse mammary epithelial cells. J Biol Chem 271:404–412

    Article  PubMed  CAS  Google Scholar 

  164. Sasson R, Shinder V, Dantes A, Land A, Amsterdam A (2003) Activation of multiple signal transduction pathways by glucocorticoids: protection of ovarian follicular cells against apoptosis. Biochem Biophys Res Commun 311:1047–1056

    Article  PubMed  CAS  Google Scholar 

  165. Khwaja A, Rodriguez-Viciana P, Wennstrom S, Warne PH, Downward J (1997) Matrix adhesion and Ras transformation both activate a phosphoinositide 3-OH kinase and protein kinase B/Akt cellular survival pathway. Embo J 16:2783–2793

    Article  PubMed  CAS  Google Scholar 

  166. Peluso JJ, Pappalardo A, Fernandez G (2001) E-cadherin-mediated cell contact prevents apoptosis of spontaneously immortalized granulosa cells by regulating Akt kinase activity. Biol Reprod 64:1183–1190

    Article  PubMed  CAS  Google Scholar 

  167. Carayol N, Vachier I, Campbell A et al (2002) Regulation of E-cadherin expression by dexamethasone and tumour necrosis factor-alpha in nasal epithelium. Eur Respir J 20:1430–1436

    Article  PubMed  CAS  Google Scholar 

  168. Song G, Ouyang G, Bao S (2005) The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med 9:59–71

    PubMed  CAS  Google Scholar 

  169. Cox AD, Der CJ (2003) The dark side of Ras: regulation of apoptosis. Oncogene 22:8999–9006

    Article  PubMed  CAS  Google Scholar 

  170. Hafezi-Moghadam A, Simoncini T, Yang Z et al (2002) Acute cardiovascular protective effects of corticosteroids are mediated by non-transcriptional activation of endothelial nitric oxide synthase. Nat Med 8:473–479

    Article  PubMed  CAS  Google Scholar 

  171. Cardone MH, Roy N, Stennicke HR et al (1998) Regulation of cell death protease caspase-9 by phosphorylation. Science 282:1318–1321

    Article  PubMed  CAS  Google Scholar 

  172. del Peso L, Gonzalez-Garcia M, Page C, Herrera R, Nunez G (1997) Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science 278:687–689

    Article  PubMed  CAS  Google Scholar 

  173. Datta SR, Dudek H, Tao X et al (1997) Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91:231–241

    Article  PubMed  CAS  Google Scholar 

  174. Wang JM, Chao JR, Chen W, Kuo ML, Yen JJ, Yang-Yen HF (1999) The antiapoptotic gene mcl-1 is up-regulated by the phosphatidylinositol 3-kinase/Akt signaling pathway through a transcription factor complex containing CREB. Mol Cell Biol 19:6195–6206

    PubMed  CAS  Google Scholar 

  175. Herr I, Debatin K-M (2001) Cellular stress response and apoptosis in cancer therapy. Blood 98:2603–2614

    Article  PubMed  CAS  Google Scholar 

  176. Huang Y, Johnson KR, Norris JS, Fan W (2000) Nuclear factor-kappaB/IkappaB signaling pathway may contribute to the mediation of paclitaxel-induced apoptosis in solid tumor cells. Cancer Res 60:4426–4432

    PubMed  CAS  Google Scholar 

  177. Karin M (1999) How NF-kB is activated: the role of the IkB kinase (IKK) complex. Oncogene 18:6867–6874

    Article  PubMed  CAS  Google Scholar 

  178. Machuca C, Mendoza-Milla C, Cordova E et al (2006) Dexamethasone protection from TNF-alpha-induced cell death in MCF-7 cells requires NF-kappaB and is independent from AKT. BMC Cell Biol 7:9

    Article  PubMed  CAS  Google Scholar 

  179. Fan W, Sui M, Huang Y (2004) Glucocorticoids selectively inhibit paclitaxel-induced apoptosis: mechanisms and its clinical impact. Curr Med Chem 11:403–411

    Article  PubMed  CAS  Google Scholar 

  180. Kane LP, Shapiro VS, Stokoe D, Weiss A (1999) Induction of NF-kappaB by the Akt/PKB kinase. Curr Biol 9:601–604

    Article  PubMed  CAS  Google Scholar 

  181. Barkett M, Gilmore TD (1999) Control of apoptosis by Rel/NF-kB transcription factors. Oncogene 18:6910–6924

    Article  PubMed  CAS  Google Scholar 

  182. Lauder A, Castellanos A, Weston K (2001) c-Myb transcription is activated by protein kinase B (PKB) following interleukin 2 stimulation of Tcells and is required for PKB-mediated protection from apoptosis. Mol Cell Biol 21:5797–5805

    Article  PubMed  CAS  Google Scholar 

  183. Pastorino JG, Tafani M, Farber JL (1999) Tumor necrosis factor induces phosphorylation and translocation of BAD through a phosphatidylinositide-3-OH kinase-dependent pathway. J Biol Chem 274:19411–19416

    Article  PubMed  CAS  Google Scholar 

  184. Madge LA, Pober JS (2000) A phosphatidylinositol 3-kinase/Akt pathway, activated by tumor necrosis factor or interleukin-1, inhibits apoptosis but does not activate NFkappaB in human endothelial cells. J Biol Chem 275:15458–15465

    Article  PubMed  CAS  Google Scholar 

  185. Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB (1999) NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature 401:82–85

    Article  PubMed  CAS  Google Scholar 

  186. Reddy SA, Huang JH, Liao WS (2000) Phosphatidylinositol 3-kinase as a mediator of TNF-induced NF-kappa B activation. J Immunol 164:1355–1363

    PubMed  CAS  Google Scholar 

  187. Gustin JA, Ozes ON, Akca H et al (2004) Cell type-specific expression of the IkappaB kinases determines the significance of phosphatidylinositol 3-kinase/Akt signaling to NF-kappa B activation. J Biol Chem 279:1615–1620

    Article  PubMed  CAS  Google Scholar 

  188. Lang F, Cohen P (2001) Regulation and physiological roles of serum- and glucocorticoid-induced protein kinase isoforms. Sci STKE 2001:RE17

    Article  PubMed  CAS  Google Scholar 

  189. Belova L, Sharma S, Brickley DR, Nicolarsen JR, Patterson C, Conzen SD (2006) Ubiquitin/proteasome degradation of serum and glucocorticoid-regulated kinase-1 (SGK-1) is mediated by the chaperone-dependent E3 ligase CHIP. Biochem J

  190. Kobayashi T, Deak M, Morrice N, Cohen P (1999) Characterization of the structure and regulation of two novel isoforms of serum- and glucocorticoid-induced protein kinase. Biochem J 344(Pt 1):189–197

    Article  PubMed  CAS  Google Scholar 

  191. Brunet A, Park J, Tran H, Hu LS, Hemmings BA, Greenberg ME (2001) Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a). Mol Cell Biol 21:952–965

    Article  PubMed  CAS  Google Scholar 

  192. Leong ML, Maiyar AC, Kim B, O’Keeffe BA, Firestone GL (2003) Expression of the serum- and glucocorticoid-inducible protein kinase, Sgk, is a cell survival response to multiple types of environmental stress stimuli in mammary epithelial cells. J Biol Chem 278:5871–5882

    Article  PubMed  CAS  Google Scholar 

  193. Hertweck M, Gobel C, Baumeister R (2004) C. elegans SGK-1 is the critical component in the Akt/PKB kinase complex to control stress response and life span. Dev Cell 6:577–588

    Article  PubMed  CAS  Google Scholar 

  194. Magi-Galluzzi C, Mishra R, Fiorentino M et al (1997) Mitogen-activated protein kinase phosphatase 1 is overexpressed in prostate cancers and is inversely related to apoptosis. Lab Invest 76:37–51

    PubMed  CAS  Google Scholar 

  195. Loda M, Capodieci P, Mishra R et al (1996) Expression of mitogen-activated protein kinase phosphatase-1 in the early phases of human epithelial carcinogenesis. Am J Pathol 149:1553–1564

    PubMed  CAS  Google Scholar 

  196. Srikanth S, Franklin CC, Duke RC, Kraft RS (1999) Human DU145 prostate cancer cells overexpressing mitogen-activated protein kinase phosphatase-1 are resistant to Fas ligand-induced mitochondrial perturbations and cellular apoptosis. Mol Cell Biochem 199:169–178

    Article  PubMed  CAS  Google Scholar 

  197. Steinmetz R, Wagoner HA, Zeng P et al (2004) Mechanisms regulating the constitutive activation of the extracellular signal-regulated kinase (ERK) signaling pathway in ovarian cancer and the effect of ribonucleic acid interference for ERK1/2 on cancer cell proliferation. Mol Endocrinol 18:2570–2582

    Article  PubMed  CAS  Google Scholar 

  198. Engelbrecht Y, de Wet H, Horsch K, Langeveldt CR, Hough FS, Hulley PA (2003) Glucocorticoids induce rapid up-regulation of mitogen-activated protein kinase phosphatase-1 and dephosphorylation of extracellular signal-regulated kinase and impair proliferation in human and mouse osteoblast cell lines. Endocrinology 144:412–422

    Article  PubMed  CAS  Google Scholar 

  199. Hamdi M, Kool J, Cornelissen-Steijger P et al (2005) DNA damage in transcribed genes induces apoptosis via the JNK pathway and the JNK-phosphatase MKP-1. Oncogene 24:7135–7134

    Article  PubMed  CAS  Google Scholar 

  200. Kim AH, Khursigara G, Sun X, Franke TF, Chao MV (2001) Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1. Mol Cell Biol 21:893–901

    Article  PubMed  CAS  Google Scholar 

  201. Barthwal MK, Sathyanarayana P, Kundu CN et al (2003) Negative regulation of mixed lineage kinase 3 by protein kinase B/AKT leads to cell survival. J Biol Chem 278:3897–3902

    Article  PubMed  CAS  Google Scholar 

  202. Park HS, Kim MS, Huh SH et al (2002) Akt (protein kinase B) negatively regulates SEK1 by means of protein phosphorylation. J Biol Chem 277:2573–2578

    Article  PubMed  CAS  Google Scholar 

  203. Desbois-Mouthon C, Cadoret A, Blivet-Van Eggelpoel MJ et al (2000) Insulin-mediated cell proliferation and survival involve inhibition of c-Jun N-terminal kinases through a phosphatidylinositol 3-kinase- and mitogen-activated protein kinase phosphatase-1-dependent pathway. Endocrinology 141:922–931

    Article  PubMed  CAS  Google Scholar 

  204. Burgering BM, Medema RH (2003) Decisions on life and death: FOXO Forkhead transcription factors are in command when PKB/Akt is off duty. J Leukoc Biol 73:689–701

    Article  PubMed  CAS  Google Scholar 

  205. Giles RH, van Es JH, Clevers H (2003) Caught up in a Wnt storm: Wnt signaling in cancer. Biochim Biophys Acta 1653:1–24

    PubMed  CAS  Google Scholar 

  206. Mulholland DJ, Dedhar S, Coetzee GA, Nelson CC (2005) Interaction of Nuclear Receptors with Wnt/beta-catenin/Tcf Signalling: Wnt you like to know? Endocr Rev 7:898–915

    Article  CAS  Google Scholar 

  207. 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 107:519–527

    Article  PubMed  CAS  Google Scholar 

  208. Woodgett JR (1990) Molecular cloning and expression of glycogen synthase kinase-3/factor A. Embo J 9:2431–2438

    PubMed  CAS  Google Scholar 

  209. Pap M, Cooper GM (1998) Role of glycogen synthase kinase-3 in the phosphatidylinositol 3-Kinase/Akt cell survival pathway. J Biol Chem 273:19929–19932

    Article  PubMed  CAS  Google Scholar 

  210. Doble BW, Woodgett JR (2003) GSK-3: tricks of the trade for a multi-tasking kinase. J Cell Sci 116:1175–1186

    Article  PubMed  CAS  Google Scholar 

  211. Harwood AJ (2001) Regulation of GSK-3: a cellular multiprocessor. Cell 105:821–824

    Article  PubMed  CAS  Google Scholar 

  212. Rathmell JC, Fox CJ, Plas DR, Hammerman PS, Cinalli RM, Thompson CB (2003) Akt-directed glucose metabolism can prevent Bax conformation change and promote growth factor-independent survival. Mol Cell Biol 23:7315–7328

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  214. Nakae J, Park BC, Accili D (1999) Insulin stimulates phosphorylation of the forkhead transcription factor FKHR on serine 253 through a Wortmannin-sensitive pathway. J Biol Chem 274:15982–15985

    Article  PubMed  CAS  Google Scholar 

  215. Edinger AL, Thompson CB (2002) Akt maintains cell size and survival by increasing mTOR-dependent nutrient uptake. Mol Biol Cell 13:2276–2288

    Article  PubMed  CAS  Google Scholar 

  216. Vander Heiden MG, Plas DR, Rathmell JC, Fox CJ, Harris MH, Thompson CB (2001) Growth factors can influence cell growth and survival through effects on glucose metabolism. Mol Cell Biol 21:5899–5912

    Article  PubMed  CAS  Google Scholar 

  217. 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 378:785–789

    Article  PubMed  CAS  Google Scholar 

  218. van Noort M, Meeldijk J, Van Der Zee R, Destree O, Clevers H (2002) Wnt signaling controls the phosphorylation status of beta-catenin. J Biol Chem 277:17901–17905

    Article  PubMed  CAS  Google Scholar 

  219. Hinoi T, Yamamoto H, Kishida M, Takada S, Kishida S, Kikuchi A (2000) Complex formation of adenomatous polyposis coli gene product and axin facilitates glycogen synthase kinase-3 beta-dependent phosphorylation of beta-catenin and down-regulates beta-catenin. J Biol Chem 275:34399–34406

    Article  PubMed  CAS  Google Scholar 

  220. Dihlmann S, von Knebel Doeberitz M (2005) Wnt/beta-catenin-pathway as a molecular target for future anti-cancer therapeutics. Int J Cancer 113:515–524

    Article  PubMed  CAS  Google Scholar 

  221. Tao YS, Edwards RA, Tubb B, Wang S, Bryan J, McCrea PD (1996) beta-Catenin associates with the actin-bundling protein fascin in a noncadherin complex. J Cell Biol 134:1271–1281

    Article  PubMed  CAS  Google Scholar 

  222. Wong V, Ching D, McCrea PD, Firestone GL (1999) Glucocorticoid down-regulation of fascin protein expression is required for the steroid-induced formation of tight junctions and cell-cell interactions in rat mammary epithelial tumor cells. J Biol Chem 274:5443–5453

    Article  PubMed  CAS  Google Scholar 

  223. Guan Y, Rubenstein NM, Failor KL, Woo PL, Firestone GL (2004) Glucocorticoids control beta-catenin protein expression and localization through distinct pathways that can be uncoupled by disruption of signaling events required for tight junction formation in rat mammary epithelial tumor cells. Mol Endocrinol 18:214–227

    Article  PubMed  CAS  Google Scholar 

  224. Zettl KS, Sjaastad MD, Riskin PM, Parry G, Machen TE, Firestone GL (1992) Glucocorticoid-induced formation of tight junctions in mouse mammary epithelial cells in vitro. Proc Natl Acad Sci USA 89:9069–9073

    Article  PubMed  CAS  Google Scholar 

  225. Buse P, Woo PL, Alexander DB et al (1995) Transforming growth factor-alpha abrogates glucocorticoid-stimulated tight junction formation and growth suppression in rat mammary epithelial tumor cells. J Biol Chem 270:6505–6514

    Article  PubMed  CAS  Google Scholar 

  226. Buse P, Woo PL, Alexander DB, Reza A, Firestone GL (1995) Glucocorticoid-induced functional polarity of growth factor responsiveness regulates tight junction dynamics in transformed mammary epithelial tumor cells. J Biol Chem 270:28223–28227

    Article  PubMed  CAS  Google Scholar 

  227. Polakis P (2000) Wnt signaling and cancer. Genes Dev 14:1837–1851

    PubMed  CAS  Google Scholar 

  228. Oren M (2003) Decision making by p53: life, death and cancer. Cell Death Differ 10:431–442

    Article  PubMed  CAS  Google Scholar 

  229. Maiyar AC, Phu PT, Huang AJ, Firestone GL (1997) Repression of glucocorticoid receptor transactivation and DNA binding of a glucocorticoid response element within the serum/glucocorticoid-inducible protein kinase (sgk) gene promoter by the p53 tumor suppressor protein. Mol Endocrinol 11:312–329

    Article  PubMed  CAS  Google Scholar 

  230. Mayo LD, Donner DB (2001) A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc Natl Acad Sci USA 98:11598–11603

    Article  PubMed  CAS  Google Scholar 

  231. Gottlieb TM, Leal JF, Seger R, Taya Y, Oren M (2002) Cross-talk between Akt, p53 and Mdm2: possible implications for the regulation of apoptosis. Oncogene 21:1299–1303

    Article  PubMed  CAS  Google Scholar 

  232. Mueller M, Strand S, Hug H et al (1997) Drug-induced apoptosis in hepatoma cells is mediated by the CD95 (APO-1/Fas) receptor/ligand system and involves activation of wild-type p53. J Clin Invest 99:403–413

    Article  CAS  Google Scholar 

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  1. Department of Surgery, University of Heidelberg, Heidelberg, Germany

    Ingrid Herr, Helmut Friess & Markus W. Büchler

  2. Experimental Surgery/Molecular OncoSurgery, University and German Cancer Research Center Heidelberg, Im Neuenheimer Feld 365, 69120, Heidelberg, Germany

    Ingrid Herr

  3. Institute of Pathology, University Hospital RWTH Aachen, Germany

    Nikolaus Gassler

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Herr, I., Gassler, N., Friess, H. et al. Regulation of differential pro- and anti-apoptotic signaling by glucocorticoids. Apoptosis 12, 271–291 (2007). https://doi.org/10.1007/s10495-006-0624-5

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