Protein kinase networks regulating glucocorticoid-induced apoptosis of hematopoietic cancer cells: Fundamental aspects and practical considerations

Leukemia and Lymphoma

Volumn 51, Issue 11, 2010, Pages 1968-2005

  Kfir Erenfeld, Shlomit ^a   Sionov, Ronit Vogt ^a   Spokoini, Rachel ^a   Cohen, Orly ^a   Yefenof, Eitan ^a  

^a HEBREW UNIVERSITY   (Israel)

Author keywords

Akt; apoptosis; glucocorticoids; glycogen synthase kinase 3; leukemia; lymphoma; mTOR; multiple myeloma; Notch1

Indexed keywords

1,4 DIAMINO 1,4 BIS(2 AMINOPHENYLTHIO) 2,3 DICYANOBUTADIENE; 2 (2 AMINO 3 METHOXYPHENYL)CHROMONE; 2 MORPHOLINO 8 PHENYLCHROMONE; 2,4 DIMETHYL 5 (2 OXO 1H INDOL 3 YLMETHYLENE) 3 PYRROLEPROPIONIC ACID; 4 AMINO 7 TERT BUTYL 5 (4 CHLOROPHENYL)PYRAZOLO[3,4 D]PYRIMIDINE; 4 AMINO 7 TERT BUTYL 5 (4 METHYLPHENYL)PYRAZOLO[3,4 D]PYRIMIDINE; A 443654; ADENYLATE KINASE; ANTHRA[1,9 CD]PYRAZOL 6(2H) ONE; ANTINEOPLASTIC AGENT; BIM PROTEIN; CYCLIC AMP; DASATINIB; DEFOROLIMUS; DOVITINIB; DUAL SPECIFICITY PHOSPHATASE; EVEROLIMUS; FORSKOLIN; GLUCOCORTICOID; GLUCOCORTICOID RECEPTOR; GLYCOGEN SYNTHASE KINASE 3; IMATINIB; INCB 16562; MAMMALIAN TARGET OF RAPAMYCIN; MITOGEN ACTIVATED PROTEIN KINASE; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN BCL 2; PROTEIN KINASE B; RAF PROTEIN; RAPAMYCIN; RAS PROTEIN; SEMAXANIB; STAUROSPORINE; STRESS ACTIVATED PROTEIN KINASE; SU 11657; SUNITINIB; SYNAPTOPHYSIN; TEMSIROLIMUS; THIOREDOXIN INTERACTING PROTEIN; TRANSCRIPTION FACTOR FOXO; UNCLASSIFIED DRUG; UNINDEXED DRUG; UNTRANSLATED RNA;

ACUTE LEUKEMIA; ACUTE LYMPHOBLASTIC LEUKEMIA; ACUTE LYMPHOCYTIC LEUKEMIA; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; CANCER CELL; CANCER RESISTANCE; CELL DEATH; CELL SURVIVAL; CHEMOSENSITIVITY; CHILDHOOD LEUKEMIA; CLINICAL PROTOCOL; DNA POLYMORPHISM; DOWN REGULATION; ENZYME ACTIVATION; EXON; GENE CONTROL; GENE MUTATION; GENETIC TRANSCRIPTION; HEMATOLOGIC MALIGNANCY; HUMAN; IMMUNOREGULATION; JUVENILE MYELOMONOCYTIC LEUKEMIA; LEUKEMIA CELL; LYMPHOID CELL; MITOCHONDRION; MOLECULAR MECHANICS; MULTIPLE MYELOMA; NONHODGKIN LYMPHOMA; PRIORITY JOURNAL; PROGNOSIS; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN LOCALIZATION; PROTEIN PROCESSING; PROTEIN PROTEIN INTERACTION; REVIEW; SIGNAL TRANSDUCTION; THYMOCYTE; TREATMENT FAILURE; UPREGULATION;

ANIMALS; APOPTOSIS; GENE REGULATORY NETWORKS; GLUCOCORTICOIDS; HEMATOLOGIC NEOPLASMS; HUMANS; MODELS, BIOLOGICAL; MOLECULAR TARGETED THERAPY; PROTEIN KINASES;

EID: 78649269460     PISSN: 10428194     EISSN: 10292403     Source Type: Journal    
DOI: 10.3109/10428194.2010.506570     Document Type: Review

References (488)

1. Sionov RV, Spokoini R, Kfir-Erenfeld S, Cohen O, Yefenof E. Mechanisms regulating the susceptibility of hematopoietic malignancies to glucocorticoid-induced apoptosis. Adv Cancer Res 2008;101:127-248.
2. Alexanian R, Barlogie B, Tucker S. VAD-based regimens as primary treatment for multiple myeloma. Am J Hematol 1990;33:86-89.
3. George ED, Sadovsky R. Multiple myeloma: recognition and management. Am Fam Physician 1999;59:1885-1894.
4. Cavo M, Zamagni E, Tosi P, et al. Superiority of thalidomide and dexamethasone over vincristine-doxorubicin-dexamethasone (VAD) as primary therapy in preparation for autologous transplantation for multiple myeloma. Blood 2005;106:35-39.
5. Dimopoulos MA, Chen C, Spencer A, et al. Long-term follow-up on overall survival from the MM-009 and MM-010 phase III trials of lenalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma. Leukemia 2009;23:2147-2152.
6. Harousseau JL, Attal M, Leleu X, et al. Bortezomib plus dexamethasone as induction treatment prior to autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: results of an IFM phase II study. Haematologica 2006;91:1498-1505.
7. Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005;352:2487-2498.
8. Jagannath S, Durie BG, Wolf J, et al. Bortezomib therapy alone and in combination with dexamethasone for previously untreated symptomatic multiple myeloma. Br J Haematol 2005;129:776-783.
9. Mitsiades CS, Hideshima T, Chauhan D, et al. Emerging treatments for multiple myeloma: beyond immunomodulatory drugs and bortezomib. Semin Hematol 2009;46:166-175.
10. Reece DE. An update of the management of multiple myeloma: the changing landscape. Hematology Am Soc Hematol Educ Program 2005:353-359.
11. Klumper E, Pieters R, Veerman AJ, et al. In vitro cellular drug resistance in children with relapsed/refractory acute lymphoblastic leukemia. Blood 1995;86:3861-3868.
12. Hongo T, Yajima S, Sakurai M, Horikoshi Y, Hanada R. In vitro drug sensitivity testing can predict induction failure and early relapse of childhood acute lymphoblastic leukemia. Blood 1997;89:2959-2965.
13. Hamilton A, Gallipoli P, Nicholson E, Holyoake TL. Targeted therapy in haematological malignancies. J Pathol 2010;220:404-418.
14. Hama S, Arita K, Nishisaka T, et al. Changes in the epithelium of Rathke cleft cyst associated with inflammation. J Neurosurg 2002;96:209-216.
15. Sionov RV. [The kinome and glucocorticoid-induced apoptosis]. Ai Zheng 2008;27:1121-1129.
16. Pratt WB, Toft DO. Regulation of signaling protein function and trafficking by the hsp90/hsp70-based chaperone machinery. Exp Biol Med (Maywood) 2003;228:111-133.
17. Pratt WB, Morishima Y, Murphy M, Harrell M. Chaperoning of glucocorticoid receptors. Handb Exp Pharmacol 2006:111-138.
18. Cheung J, Smith DF. Molecular chaperone interactions with steroid receptors: an update. Mol Endocrinol 2000;14:939-946.
19. Croxtall JD, Choudhury Q, Flower RJ. Glucocorticoids act within minutes to inhibit recruitment of signalling factors to activated EGF receptors through a receptor-dependent, transcription-independent mechanism. Br J Pharmacol 2000;130:289-298.
20. Davies TH, Ning YM, Sanchez ER. A new first step in activation of steroid receptors: hormone-induced switching of FKBP51 and FKBP52 immunophilins. J Biol Chem 2002;277:4597-4600.
21. Bledsoe RK, Montana VG, Stanley TB, et al. Crystal structure of the glucocorticoid receptor ligand binding domain reveals a novel mode of receptor dimerization and coactivator recognition. Cell 2002;110:93-105.
22. Freedman ND, Yamamoto KR. Importin 7 and importin alpha/importin beta are nuclear import receptors for the glucocorticoid receptor. Mol Biol Cell 2004;15:2276-2286.
23. van der Laan S, Meijer OC. Pharmacology of glucocorticoids: beyond receptors. Eur J Pharmacol 2008;585:483-491.
24. Zhang G, Zhang L, Duff GW. A negative regulatory region containing a glucocorticosteroid response element (nGRE) in the human interleukin-1beta gene. DNA Cell Biol 1997;16:145-152.
25. Sakai DD, Helms S, Carlstedt-Duke J, Gustafsson JA, Rottman FM, Yamamoto KR. Hormone-mediated repression: a negative glucocorticoid response element from the bovine prolactin gene. Genes Dev 1988;2:1144-1154.
26. Drouin J, Sun YL, Chamberland M, et al. Novel glucocorticoid receptor complex with DNA element of the hormonerepressed POMC gene. EMBO J 1993;12:145-156.
27. Malkoski SP, Dorin RI. Composite glucocorticoid regulation at a functionally defined negative glucocorticoid response element of the human corticotropin-releasing hormone gene. Mol Endocrinol 1999;13:1629-1644.
28. Meyer T, Gustafsson JA, Carlstedt-Duke J. Glucocorticoiddependent transcriptional repression of the osteocalcin gene by competitive binding at the TATA box. DNA Cell Biol 1997;16:919-927.
29. Dostert A, Heinzel T. Negative glucocorticoid receptor response elements and their role in glucocorticoid action. Curr Pharm Des 2004;10:2807-2816.
30. Novac N, Baus D, Dostert A, Heinzel T. Competition between glucocorticoid receptor and NFkappaB for control of the human FasL promoter. FASEB J 2006;20:1074-1081.
31. Wallberg AE, Neely KE, Hassan AH, Gustafsson JA, Workman JL, Wright AP. Recruitment of the SWI-SNF chromatin remodeling complex as a mechanism of gene activation by the glucocorticoid receptor tau1 activation domain. Mol Cell Biol 2000;20:2004-2013.
32. Ostlund Farrants AK, Blomquist P, Kwon H, Wrange O. Glucocorticoid receptor-glucocorticoid response element binding stimulates nucleosome disruption by the SWI/SNF complex. Mol Cell Biol 1997;17:895-905.
33. Pottier N, Yang W, Assem M, et al. The SWI/SNF chromatin-remodeling complex and glucocorticoid resistance in acute lymphoblastic leukemia. J Natl Cancer Inst 2008;100:1792-1803.
34. Horie-Inoue K, Takayama K, Bono HU, Ouchi Y, Okazaki Y, Inoue S. Identification of novel steroid target genes through the combination of bioinformatics and functional analysis of hormone response elements. Biochem Biophys Res Commun 2006;339:99-106.
35. So AY, Chaivorapol C, Bolton EC, Li H, Yamamoto KR. Determinants of cell- and gene-specific transcriptional regulation by the glucocorticoid receptor. PLoS Genet 2007;3:e94.
36. De Bosscher K, Haegeman G. Minireview: latest perspectives on antiinflammatory actions of glucocorticoids. Mol Endocrinol 2009;23:281-291.
37. Tissing WJ, den Boer ML, Meijerink JP, et al. Genomewide identification of prednisolone-responsive genes in acute lymphoblastic leukemia cells. Blood 2007;109:3929-3935.
38. Wang Z, Malone MH, He H, McColl KS, Distelhorst CW. Microarray analysis uncovers the induction of the proapoptotic BH3-only protein Bim in multiple models of glucocorticoid-induced apoptosis. J Biol Chem 2003;278:23861-23867.
39. Zhang L, Insel PA. The pro-apoptotic protein Bim is a convergence point for cAMP/protein kinase A- and glucocorticoid-promoted apoptosis of lymphoid cells. J Biol Chem 2004;279:20858-20865.
40. Villunger A, Michalak EM, Coultas L, et al. p53- and druginduced apoptotic responses mediated by BH3-only proteins puma and noxa. Science 2003;302:1036-1038.
41. Lynch JT, Rajendran R, Xenaki G, Berrou I, Demonacos C, Krstic-Demonacos M. The role of glucocorticoid receptor phosphorylation in Mcl-1 and NOXA gene expression. Mol Cancer 2010;9:38.
42. Ploner C, Rainer J, Niederegger H, et al. The BCL2 rheostat in glucocorticoid-induced apoptosis of acute lymphoblastic leukemia. Leukemia 2008;22:370-377.
43. Yoshida NL, Miyashita T, U M, et al. Analysis of gene expression patterns during glucocorticoid-induced apoptosis using oligonucleotide arrays. Biochem Biophys Res Commun 2002;293:1254-1261.
44. Myoumoto A, Nakatani K, Koshimizu TA, Matsubara H, Adachi S, Tsujimoto G. Glucocorticoid-induced granzyme A expression can be used as a marker of glucocorticoid sensitivity for acute lymphoblastic leukemia therapy. J Hum Genet 2007;52:328-333.
45. Yamada M, Hirasawa A, Shiojima S, Tsujimoto G. Granzyme A mediates glucocorticoid-induced apoptosis in leukemia cells. FASEB J 2003;17:1712-1714.
46. Wang Z, Rong YP, Malone MH, Davis MC, Zhong F, Distelhorst CW. Thioredoxin-interacting protein (txnip) is a glucocorticoid-regulated primary response gene involved in mediating glucocorticoid-induced apoptosis. Oncogene 2006;25:1903-1913.
47. Malone MH, Wang Z, Distelhorst CW. The glucocorticoid-induced gene tdag8 encodes a pro-apoptotic G protein-coupled receptor whose activation promotes glucocorticoid-induced apoptosis. J Biol Chem 2004;279:52850-52859.
48. Woodward MJ, de Boer J, Heidorn S, et al. Tnfaip8 is an essential gene for the regulation of glucocorticoid-mediated apoptosis of thymocytes. Cell Death Differ 2010;17:316-323.
49. D'Adamio F, Zollo O, Moraca R, et al. A new dexamethasone-induced gene of the leucine zipper family protects T lymphocytes from TCR/CD3-activated cell death. Immunity 1997;7:803-812.
50. Ayroldi E, Riccardi C. Glucocorticoid-induced leucine zipper (GILZ): a new important mediator of glucocorticoid action. FASEB J 2009;23:3649-3658.
51. Alheim K, Corness J, Samuelsson MK, et al. Identification of a functional glucocorticoid response element in the promoter of the cyclin-dependent kinase inhibitor p57Kip2. J Mol Endocrinol 2003;30:359-368.
52. Schmidt S, Rainer J, Ploner C, Presul E, Riml S, Kofler R. Glucocorticoid-induced apoptosis and glucocorticoid resistance: molecular mechanisms and clinical relevance. Cell Death Differ 2004;11(Suppl. 1):S45-S55.
53. Kassel O, Sancono A, Kratzschmar J, Kreft B, Stassen M, Cato AC. Glucocorticoids inhibit MAP kinase via increased expression and decreased degradation of MKP-1. EMBO J 2001;20:7108-7116.
54. Tchen CR, Martins JR, Paktiawal N, Perelli R, Saklatvala J, Clark AR. Glucocorticoid regulation of mouse and human dual specificity phosphatase 1 (DUSP1) genes: unusual cisacting elements and unexpected evolutionary divergence. J Biol Chem 2010;285:2642-2652.
55. Miller AL, Komak S, Webb MS, Leiter EH, Thompson EB. Gene expression profiling of leukemic cells and primary thymocytes predicts a signature for apoptotic sensitivity to glucocorticoids. Cancer Cell Int 2007;7:18.
56. Bouillet P, Metcalf D, Huang DC, et al. Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science 1999;286:1735-1738.
57. Abrams MT, Robertson NM, Yoon K, Wickstrom E. Inhibition of glucocorticoid-induced apoptosis by targeting the major splice variants of BIM mRNA with small interfering RNA and short hairpin RNA. J Biol Chem 2004;279:55809-55817.
58. Lopez-Royuela N, Balsas P, Galan-Malo P, Anel A, Marzo I, Naval J. Bim is the key mediator of glucocorticoidinduced apoptosis and of its potentiation by rapamycin in human myeloma cells. Biochim Biophys Acta 2010;1803:311-322.
59. Lu J, Quearry B, Harada H. p38-MAP kinase activation followed by BIM induction is essential for glucocorticoidinduced apoptosis in lymphoblastic leukemia cells. FEBS Lett 2006;580:3539-3544.
60. Rambal AA, Panaguiton ZL, Kramer L, Grant S, Harada H. MEK inhibitors potentiate dexamethasone lethality in acute lymphoblastic leukemia cells through the pro-apoptotic molecule BIM. Leukemia 2009;23:1744-1754.
61. Espina B, Liang M, Russell RG, Hulley PA. Regulation of bim in glucocorticoid-mediated osteoblast apoptosis. J Cell Physiol 2008;215:488-496.
62. Sionov RV, Kfir S, Zafrir E, Cohen O, Zilberman Y, Yefenof E. Glucocorticoid-induced apoptosis revisited: a novel role for glucocorticoid receptor translocation to the mitochondria. Cell Cycle 2006;5:1017-1026.
63. Kfir S, Sionov RV, Zafrir E, Zilberman Y, Yefenof E. Staurosporine sensitizes T lymphoma cells to glucocorticoidinduced apoptosis: role of Nur77 and Bcl-2. Cell Cycle 2007;6:3086-3096.
64. Adachi M, Zhao X, Imai K. Nomenclature of dynein light chain-linked BH3-only protein Bim isoforms. Cell Death Differ 2005;12:192-193.
65. O'Connor L, Strasser A, O'Reilly LA, et al. Bim: a novel member of the Bcl-2 family that promotes apoptosis. EMBO J 1998;17:384-395.
66. Zhao YN, Li Q, Yang K. [Role of pro-apoptotic protein Bim in mouse thymocytes apoptosis induced by dexamethasone]. Sichuan Da Xue Xue Bao Yi Xue Ban 2007;38:851-855.
67. Iglesias-Serret D, de Frias M, Santidrian AF, et al. Regulation of the proapoptotic BH3-only protein BIM by glucocorticoids, survival signals and proteasome in chronic lymphocytic leukemia cells. Leukemia 2007;21:281-287.
68. Spokoini R, Kfir-Erenfeld S, Yefenof E, Sionov RV. Glycogen synthase kinase-3 plays a central role in mediating glucocorticoid-induced apoptosis. Mol Endocrinol 2010;24:1136-1150.
69. Bachmann PS, Gorman R, Papa RA, et al. Divergent mechanisms of glucocorticoid resistance in experimental models of pediatric acute lymphoblastic leukemia. Cancer Res 2007;67:4482-4490.
70. Lomonosova E, Chinnadurai G. BH3-only proteins in apoptosis and beyond: an overview. Oncogene 2008;27(Suppl. 1):S2-S19.
71. Rathmell JC, Lindsten T, Zong WX, Cinalli RM, Thompson CB. Deficiency in Bak and Bax perturbs thymic selection and lymphoid homeostasis. Nat Immunol 2002;3:932-939.
72. Laane E, Panaretakis T, Pokrovskaja K, et al. Dexamethasone-induced apoptosis in acute lymphoblastic leukemia involves differential regulation of Bcl-2 family members. Haematologica 2007;92:1460-1469.
73. Marani M, Tenev T, Hancock D, Downward J, Lemoine NR. Identification of novel isoforms of the BH3 domain protein Bim which directly activate Bax to trigger apoptosis. Mol Cell Biol 2002;22:3577-3589.
74. Gavathiotis E, Suzuki M, Davis ML, et al. BAX activation is initiated at a novel interaction site. Nature 2008;455:1076-1081.
75. Czabotar PE, Colman PM, Huang DC. Bax activation by Bim? Cell Death Differ 2009;16:1187-1191.
76. Sugiyama T, Shimizu S, Matsuoka Y, Yoneda Y, Tsujimoto Y. Activation of mitochondrial voltage-dependent anion channel by apro-apoptotic BH3-only protein Bim. Oncogene 2002;21:4944-4956.
77. Terrones O, Etxebarria A, Landajuela A, Landeta O, Antonsson B, Basanez G. BIM and tBID are not mechanistically equivalent when assisting BAX to permeabilize bilayer membranes. J Biol Chem 2008;283:7790-7803.
78. Casale F, Addeo R, D'Angelo V, et al. Determination of the in vivo effects of prednisone on Bcl-2 family protein expression in childhood acute lymphoblastic leukemia. Int J Oncol 2003;22:123-128.
79. Bianchini R, Nocentini G, Krausz LT, et al. Modulation of pro- and antiapoptotic molecules in double-positive (CD4+CD8+) thymocytes following dexamethasone treatment. J Pharmacol Exp Ther 2006;319:887-897.
80. Labi V, Erlacher M, Kiessling S, et al. Loss of the BH3-only protein Bmf impairs B cell homeostasis and accelerates gamma irradiation-induced thymic lymphoma development. J Exp Med 2008;205:641-655.
81. Erlacher M, Michalak EM, Kelly PN, et al. BH3-only proteins Puma and Bim are rate-limiting for gammaradiation- and glucocorticoid-induced apoptosis of lymphoid cells in vivo. Blood 2005;106:4131-4138.
82. Tosa N, Murakami M, Jia WY, et al. Critical function of T cell death-associated gene 8 in glucocorticoid-induced thymocyte apoptosis. Int Immunol 2003;15:741-749.
83. Willis SN, Chen L, Dewson G, et al. Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins. Genes Dev 2005;19:1294-1305.
84. Akgul C. Mcl-1 is a potential therapeutic target in multiple types of cancer. Cell Mol Life Sci 2009;66:1326-1336.
85. Wei G, Twomey D, Lamb J, et al. Gene expression-based chemical genomics identifies rapamycin as a modulator of MCL1 and glucocorticoid resistance. Cancer Cell 2006;10:331-342.
86. Saffar AS, Dragon S, Ezzati P, Shan L, Gounni AS. Phosphatidylinositol 3-kinase and p38 mitogen-activated protein kinase regulate induction of Mcl-1 and survival in glucocorticoid-treated human neutrophils. J Allergy Clin Immunol 2008;121:492-498.e10.
87. Ploner C, Rainer J, Lobenwein S, Geley S, Kofler R. Repression of the BH3-only molecule PMAIP1/Noxa impairs glucocorticoid sensitivity of acute lymphoblastic leukemia cells. Apoptosis 2009;14:821-828.
88. Han SH, Jeon JH, Ju HR, et al. VDUP1 upregulated by TGF-beta1 and 1, 25-dihydorxyvitamin D3 inhibits tumor cell growth by blocking cell-cycle progression. Oncogene 2003;22:4035-4046.
89. Liu Y, Min W. Thioredoxin promotes ASK1 ubiquitination and degradation to inhibit ASK1-mediated apoptosis in a redox activity-independent manner. Circ Res 2002;90:1259-1266.
90. Junn E, Han SH, Im JY, et al. Vitamin D3 up-regulated protein 1 mediates oxidative stress via suppressing the thioredoxin function. J Immunol 2000;164:6287-6295.
91. Schulze PC, Yoshioka J, Takahashi T, He Z, King GL, Lee RT. Hyperglycemia promotes oxidative stress through inhibition of thioredoxin function by thioredoxin-interacting protein. J Biol Chem 2004;279:30369-30374.
92. Ayroldi E, Migliorati G, Bruscoli S, et al. Modulation of T-cell activation by the glucocorticoid-induced leucine zipper factor via inhibition of nuclear factor kappaB. Blood 2001;98:743-753.
93. Ayroldi E, Zollo O, Bastianelli A, et al. GILZ mediates the antiproliferative activity of glucocorticoids by negative regulation of Ras signaling. J Clin Invest 2007;117:1605-1615.
94. Latre de Late P, Pepin A, Assaf-Vandecasteele H, et al. Glucocorticoid-induced leucine zipper (GILZ) promotes the nuclear exclusion of FOXO3 in a Crm1-dependent manner. J Biol Chem 2010;285:5594-5605.
95. Abraham SM, Clark AR. Dual-specificity phosphatase 1: a critical regulator of innate immune responses. Biochem Soc Trans 2006;34:1018-1023.
96. Horsch K, de Wet H, Schuurmans MM, et al. Mitogenactivated protein kinase phosphatase 1/dual specificity phosphatase 1 mediates glucocorticoid inhibition of osteoblast proliferation. Mol Endocrinol 2007;21:2929-2940.
97. Beck IM, Vanden Berghe W, Vermeulen L, Yamamoto KR, Haegeman G, De Bosscher K. Crosstalk in inflammation: the interplay of glucocorticoid receptor-based mechanisms and kinases and phosphatases. Endocr Rev 2009;30:830-882.
98. Clark AR, Martins JR, Tchen CR. Role of dual specificity phosphatases in biological responses to glucocorticoids. J Biol Chem 2008;283:25765-25769.
99. Johansson-Haque K, Palanichamy E, Okret S. Stimulation of MAPK-phosphatase 1 gene expression by glucocorticoids occurs through a tethering mechanism involving C/EBP. J Mol Endocrinol 2008;41:239-249.
100. Bouillet P, Zhang LC, Huang DC, et al. Gene structure alternative splicing, and chromosomal localization of proapoptotic Bcl-2 relative Bim. Mamm Genome 2001;12:163-168.
101. Urbich C, Knau A, Fichtlscherer S, et al. FOXO-dependent expression of the proapoptotic protein Bim: pivotal role for apoptosis signaling in endothelial progenitor cells. FASEB J 2005;19:974-976.
102. Gilley J, Coffer PJ, Ham J. FOXO transcription factors directly activate bim gene expression and promote apoptosis in sympathetic neurons. J Cell Biol 2003;162:613-622.
103. Pinon JD, Labi V, Egle A, Villunger A. Bim and Bmf in tissue homeostasis and malignant disease. Oncogene 2008;27(Suppl. 1):S41-S52.
104. Yang JY, Hung MC. A new fork for clinical application: targeting forkhead transcription factors in cancer. Clin Cancer Res 2009;15:752-757.
105. Stahl M, Dijkers PF, Kops GJ, et al. The forkhead transcription factor FoxO regulates transcription of p27Kip1 and Bim in response to IL-2. J Immunol 2002;168:5024-5031.
106. Sunters A, Fernandez de Mattos S, Stahl M, et al. FoxO3a transcriptional regulation of Bim controls apoptosis in paclitaxel-treated breast cancer cell lines. J Biol Chem 2003;278:49795-49805.
107. Cai B, Xia Z. p38 MAP kinase mediates arsenite-induced apoptosis through FOXO3a activation and induction of Bim transcription. Apoptosis 2008;13:803-810.
108. Planey SL, Abrams MT, Robertson NM, Litwack G. Role of apical caspases and glucocorticoid-regulated genes in glucocorticoid-induced apoptosis of pre-B leukemic cells. Cancer Res 2003;63:172-178.
109. Ma J, Xie Y, Shi Y, Qin W, Zhao B, Jin Y. Glucocorticoidinduced apoptosis requires FOXO3A activity. Biochem Biophys Res Commun 2008;377:894-898.
110. Zhang X, Yong W, Lv J, et al. Inhibition of forkhead box O1 protects pancreatic beta-cells against dexamethasoneinduced dysfunction. Endocrinology 2009;150:4065-4073.
111. Asselin-Labat ML, Biola-Vidamment A, Kerbrat S, Lombes M, Bertoglio J, Pallardy M. FoxO3 mediates antagonistic effects of glucocorticoids and interleukin-2 on glucocorticoid-induced leucine zipper expression. Mol Endocrinol 2005;19:1752-1764.
112. Waddell DS, Baehr LM, van den Brandt J, et al. The glucocorticoid receptor and FOXO1 synergistically activate the skeletal muscle atrophy-associated MuRF1 gene. Am J Physiol Endocrinol Metab 2008;295:E785-E797.
113. Gan L, Pan H, Unterman TG. Insulin response sequencedependent and -independent mechanisms mediate effects of insulin on glucocorticoid-stimulated insulin-like growth factor binding protein-1 promoter activity. Endocrinology 2005;146:4274-4280.
114. Vander Kooi BT, Onuma H, Oeser JK, et al. The glucose-6-phosphatase catalytic subunit gene promoter contains both positive and negative glucocorticoid response elements. Mol Endocrinol 2005;19:3001-3022.
115. Hall RK, Wang XL, George L, Koch SR, Granner DK. Insulin represses phosphoenolpyruvate carboxykinase gene transcription by causing the rapid disruption of an active transcription complex: a potential epigenetic effect. Mol Endocrinol 2007;21:550-563.
116. Kwon HS, Huang B, Unterman TG, Harris RA. Protein kinase B-alpha inhibits human pyruvate dehydrogenase kinase-4 gene induction by dexamethasone through inactivation of FOXO transcription factors. Diabetes 2004;53:899-910.
117. Puthanveetil P, Wang Y, Wang F, Kim MS, Abrahani A, Rodrigues B. The increase in cardiac pyruvate dehydrogenase kinase-4 after short-term dexamethasone is controlled by an Akt-p38-forkhead box other factor-1 signaling axis. Endocrinology 2010;151:2306-2318.
118. Brunet A, Bonni A, Zigmond MJ, et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 1999;96:857-868.
119. Obexer P, Geiger K, Ambros PF, Meister B, Ausserlechner MJ. FKHRL1-mediated expression of Noxa and Bim induces apoptosis via the mitochondria in neuroblastoma cells. Cell Death Differ 2007;14:534-547.
120. Li X, Rong Y, Zhang M, et al. Up-regulation of thioredoxin interacting protein (Txnip) by p38 MAPK and FOXO1 contributes to the impaired thioredoxin activity and increased ROS in glucose-treated endothelial cells. Biochem Biophys Res Commun 2009;381:660-665.
121. Essaghir A, Dif N, Marbehant CY, Coffer PJ, Demoulin JB. The transcription of FOXO genes is stimulated by FOXO3 and repressed by growth factors. J Biol Chem 2009;284:10334-10342.
122. Birkenkamp KU, Coffer PJ. Regulation of cell survival and proliferation by the FOXO (Forkhead box, class O) subfamily of Forkhead transcription factors. Biochem Soc Trans 2003;31:292-297.
123. Breslin MB, Geng CD, Vedeckis WV. Multiple promoters exist in the human GR gene, one of which is activated by glucocorticoids. Mol Endocrinol 2001;15:1381-1395.
124. Presul E, Schmidt S, Kofler R, Helmberg A. Identification, tissue expression, and glucocorticoid responsiveness of alternative first exons of the human glucocorticoid receptor. J Mol Endocrinol 2007;38:79-90.
125. Gross KL, Lu NZ, Cidlowski JA. Molecular mechanisms regulating glucocorticoid sensitivity and resistance. Mol Cell Endocrinol 2009;300:7-16.
126. Ramdas J, Liu W, Harmon JM. Glucocorticoid-induced cell death requires autoinduction of glucocorticoid receptor expression in human leukemic T cells. Cancer Res 1999;59:1378-1385.
127. van Galen JC, Kuiper RP, van Emst L, et al. BTG1 regulates glucocorticoid receptor autoinduction in acute lymphoblastic leukemia. Blood 2010;115:4810-4819.
128. Berki T, Palinkas L, Boldizsar F, Nemeth P. Glucocorticoid (GC) sensitivity and GC receptor expression differ in thymocyte subpopulations. Int Immunol 2002;14:463-469.
129. Tissing WJ, Meijerink JP, den Boer ML, Pieters R. Molecular determinants of glucocorticoid sensitivity and resistance in acute lymphoblastic leukemia. Leukemia 2003;17:17-25.
130. Wiegers GJ, Knoflach M, Bock G, et al. CD4 (+) CD8 (+) TCR (low) thymocytes express low levels of glucocorticoid receptors while being sensitive to glucocorticoidinduced apoptosis. Eur J Immunol 2001;31:2293-2301.
131. Gupta V, Thompson EB, Stock-Novack D, et al. Efficacy of prednisone in refractory multiple myeloma and measurement of glucocorticoid receptors. A Southwest Oncology Group study. Invest New Drugs 1994;12:121-128.
132. Zilberman Y, Zafrir E, Ovadia H, Yefenof E, Guy R, Sionov RV. The glucocorticoid receptor mediates the thymic epithelial cell-induced apoptosis of CD4+8+ thymic lymphoma cells. Cell Immunol 2004;227:12-23.
133. Gehring U, Mugele K, Ulrich J. Cellular receptor levels and glucocorticoid responsiveness of lymphoma cells. Mol Cell Endocrinol 1984;36:107-113.
134. Geley S, Hartmann BL, Hala M, Strasser-Wozak EM, Kapelari K, Kofler R. Resistance to glucocorticoid-induced apoptosis in human T-cell acute lymphoblastic leukemia CEM-C1 cells is due to insufficient glucocorticoid receptor expression. Cancer Res 1996;56:5033-5038.
135. Gruber G, Carlet M, Turtscher E, et al. Levels of glucocorticoid receptor and its ligand determine sensitivity and kinetics of glucocorticoid-induced leukemia apoptosis. Leukemia 2009;23:820-823.
136. Schwartz JR, Sarvaiya PJ, Vedeckis WV. Glucocorticoid receptor knock down reveals a similar apoptotic threshold but differing gene regulation patterns in T-cell and pre-B-cell acute lymphoblastic leukemia. Mol Cell Endocrinol 2010;320:76-86.
137. Baschant U, Tuckermann J. The role of the glucocorticoid receptor in inflammation and immunity. J Steroid Biochem Mol Biol 2010;120:69-75.
138. Nissen RM, Yamamoto KR. The glucocorticoid receptor inhibits NFkappaB by interfering with serine-2 phosphorylation of the RNA polymerase II carboxy-terminal domain. Genes Dev 2000;14:2314-2329.
139. Kamei Y, Xu L, Heinzel T, et al. A CBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors. Cell 1996;85:403-414.
140. Ito K, Barnes PJ, Adcock IM. Glucocorticoid receptor recruitment of histone deacetylase 2 inhibits interleukin-1beta-induced histone H4 acetylation on lysines 8 and 12. Mol Cell Biol 2000;20:6891-6903.
141. Auphan N, DiDonato JA, Rosette C, Helmberg A, Karin M. Immunosuppression by glucocorticoids: inhibition of NF-kappa B activity through induction of I kappa B synthesis. Science 1995;270:286-290.
142. Almawi WY, Melemedjian OK. Negative regulation of nuclear factor-kappaB activation and function by glucocorticoids. J Mol Endocrinol 2002;28:69-78.
143. Rainer J, Ploner C, Jesacher S, et al. Glucocorticoidregulated microRNAs and mirtrons in acute lymphoblastic leukemia. Leukemia 2009;23:746-752.
144. Kawashima H, Numakawa T, Kumamaru E, et al. Glucocorticoid attenuates brain-derived neurotrophic factordependent upregulation of glutamate receptors via the suppression of microRNA-132 expression. Neuroscience 2010;165:1301-1311.
145. Linsley PS, Schelter J, Burchard J, et al. Transcripts targeted by the microRNA-16 family cooperatively regulate cell cycle progression. Mol Cell Biol 2007;27:2240-2252.
146. Cimmino A, Calin GA, Fabbri M, et al. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci USA 2005;102:13944-13949.
147. Vreugdenhil E, Verissimo CS, Mariman R, et al. MicroRNA 18 and 124a down-regulate the glucocorticoid receptor: implications for glucocorticoid responsiveness in the brain. Endocrinology 2009;150:2220-2228.
148. Kotani A, Ha D, Hsieh J, et al. miR-128b is a potent glucocorticoid sensitizer in MLL-AF4 acute lymphocytic leukemia cells and exerts cooperative effects with miR-221. Blood 2009;114:4169-4178.
149. Zhou J, Cidlowski JA. The human glucocorticoid receptor: one gene, multiple proteins and diverse responses. Steroids 2005;70:407-417.
150. Kelly A, Bowen H, Jee YK, et al. The glucocorticoid receptor beta isoform can mediate transcriptional repression by recruiting histone deacetylases. J Allergy Clin Immunol 2008;121:203-208.e1.
151. Haarman EG, Kaspers GJ, Pieters R, Rottier MM, Veerman AJ. Glucocorticoid receptor alpha, beta and gamma expression vs in vitro glucocorticod resistance in childhood leukemia. Leukemia 2004;18:530-537.
152. Tissing WJ, Lauten M, Meijerink JP, et al. Expression of the glucocorticoid receptor and its isoforms in relation to glucocorticoid resistance in childhood acute lymphocytic leukemia. Haematologica 2005;90:1279-1281.
153. Koga Y, Matsuzaki A, Suminoe A, Hattori H, Kanemitsu S, Hara T. Differential mRNA expression of glucocorticoid receptor alpha and beta is associated with glucocorticoid sensitivity of acute lymphoblastic leukemia in children. Pediatr Blood Cancer 2005;45:121-127.
154. Irving JA, Minto L, Bailey S, Hall AG. Loss of heterozygosity and somatic mutations of the glucocorticoid receptor gene are rarely found at relapse in pediatric acute lymphoblastic leukemia but may occur in a subpopulation early in the disease course. Cancer Res 2005;65:9712-9718.
155. Tissing WJ, Meijerink JP, Brinkhof B, et al. Glucocorticoidinduced glucocorticoid-receptor expression and promoter usage is not linked to glucocorticoid resistance in childhood ALL. Blood 2006;108:1045-1049.
156. Tissing WJ, Meijerink JP, den Boer ML, et al. Genetic variations in the glucocorticoid receptor gene are not related to glucocorticoid resistance in childhood acute lymphoblastic leukemia. Clin Cancer Res 2005;11:6050-6056.
157. Beesley AH, Weller RE, Senanayake S, Welch M, Kees UR. Receptor mutation is not a common mechanism of naturally occurring glucocorticoid resistance in leukaemia cell lines. Leuk Res 2009;33:321-325.
158. Labuda M, Gahier A, Gagne V, Moghrabi A, Sinnett D, Krajinovic M. Polymorphisms in glucocorticoid receptor gene and the outcome of childhood acute lymphoblastic leukemia (ALL). Leuk Res 2010;34:492-497.
159. Lauten M, Fernandez-Munoz I, Gerdes K, et al. Kinetics of the in vivo expression of glucocorticoid receptor splice variants during prednisone treatment in childhood acute lymphoblastic leukaemia. Pediatr Blood Cancer 2009;52:459-463.
160. Kino T, Hurt DE, Ichijo T, Nader N, Chrousos GP. Noncoding RNA gas5 is a growth arrest- and starvation-associated repressor of the glucocorticoid receptor. Sci Signal 2010;3:ra8.
161. Mattick JS. The functional genomics of noncoding RNA. Science 2005;309:1527-1528.
162. Barrandon C, Spiluttini B, Bensaude O. Non-coding RNAs regulating the transcriptional machinery. Biol Cell 2008;100:83-95.
163. Coccia EM, Cicala C, Charlesworth A, et al. Regulation and expression of a growth arrest-specific gene (gas5) during growth, differentiation, and development. Mol Cell Biol 1992;12:3514-3521.
164. Smith CM, Steitz JA. Classification of gas5 as a multi-smallnucleolar-RNA (snoRNA) host gene and a member of the 50-terminal oligopyrimidine gene family reveals common features of snoRNA host genes. Mol Cell Biol 1998;18:6897-6909.
165. Hamilton TL, Stoneley M, Spriggs KA, Bushell M. TOPs and their regulation. Biochem Soc Trans 2006;34:12-16.
166. Mourtada-Maarabouni M, Hedge VL, Kirkham L, Farzaneh F, Williams GT. Growth arrest in human T-cells is controlled by the non-coding RNA growth-arrest-specific transcript 5 (GAS5). J Cell Sci 2008;121:939-946.
167. Ismaili N, Garabedian MJ. Modulation of glucocorticoid receptor function via phosphorylation. Ann NY Acad Sci 2004;1024:86-101.
168. Bodwell JE, Orti E, Coull JM, Pappin DJ, Smith LI, Swift F. Identification of phosphorylated sites in the mouse glucocorticoid receptor. J Biol Chem 1991;266:7549-7555.
169. Bodwell JE, Webster JC, Jewell CM, Cidlowski JA, Hu JM, Munck A. Glucocorticoid receptor phosphorylation: overview, function and cell cycle-dependence. J Steroid Biochem Mol Biol 1998;65:91-99.
170. Orti E, Hu LM, Munck A. Kinetics of glucocorticoid receptor phosphorylation in intact cells. Evidence for hormone-induced hyperphosphorylation after activation and recycling of hyperphosphorylated receptors. J Biol Chem 1993;268:7779-7784.
171. Almlof T, Wright AP, Gustafsson JA. Role of acidic and phosphorylated residues in gene activation by the glucocorticoid receptor. J Biol Chem 1995;270:17535-17540.
172. Davies L, Karthikeyan N, Lynch JT, et al. Cross talk of signaling pathways in the regulation of the glucocorticoid receptor function. Mol Endocrinol 2008;22:1331-1344.
173. Krstic MD, Rogatsky I, Yamamoto KR, Garabedian MJ. Mitogen-activated and cyclin-dependent protein kinases selectively and differentially modulate transcriptional enhancement by the glucocorticoid receptor. Mol Cell Biol 1997;17:3947-3954.
174. Rogatsky I, Waase CL, Garabedian MJ. Phosphorylation and inhibition of rat glucocorticoid receptor transcriptional activation by glycogen synthase kinase-3 (GSK-3). Speciesspecific differences between human and rat glucocorticoid receptor signaling as revealed through GSK-3 phosphorylation. J Biol Chem 1998;273:14315-14321.
175. Galliher-Beckley AJ, Williams JG, Collins JB, Cidlowski JA. Glycogen synthase kinase 3beta-mediated serine phosphorylation of the human glucocorticoid receptor redirects gene expression profiles. Mol Cell Biol 2008;28:7309-7322.
176. Wang Z, Frederick J, Garabedian MJ. Deciphering the phosphorylation 'code' of the glucocorticoid receptor in vivo. J Biol Chem 2002;277:26573-26580.
177. Miller AL, Webb MS, Copik AJ, et al. p38 Mitogen-activated protein kinase (MAPK) is a key mediator in glucocorticoidinduced apoptosis of lymphoid cells: correlation between p38 MAPK activation and site-specific phosphorylation of the human glucocorticoid receptor at serine 211. Mol Endocrinol 2005;19:1569-1583.
178. Blind RD, Garabedian MJ. Differential recruitment of glucocorticoid receptor phospho-isoforms to glucocorticoidinduced genes. J Steroid Biochem Mol Biol 2008;109:150-157.
179. Chen W, Dang T, Blind RD, et al. Glucocorticoid receptor phosphorylation differentially affects target gene expression. Mol Endocrinol 2008;22:1754-1766.
180. Wang X, Wu H, Lakdawala VS, Hu F, Hanson ND, Miller AH. Inhibition of Jun. N-terminal kinase (JNK) enhances glucocorticoid receptor-mediated function in mouse hippocampal HT22 cells. Neuropsychopharmacology 2005;30:242-249.
181. Itoh M, Adachi M, Yasui H, Takekawa M, Tanaka H, Imai K. Nuclear export of glucocorticoid receptor is enhanced by c-Jun. N-terminal kinase-mediated phosphorylation. Mol Endocrinol 2002;16:2382-2392.
182. Schaaf MJ, Cidlowski JA. Molecular mechanisms of glucocorticoid action and resistance. J Steroid Biochem Mol Biol 2002;83:37-48.
183. Wallace AD, Cidlowski JA. Proteasome-mediated glucocorticoid receptor degradation restricts transcriptional signaling by glucocorticoids. J Biol Chem 2001;276:42714-42721.
184. Cai B, Chang SH, Becker EB, Bonni A, Xia Z. p38 MAP kinase mediates apoptosis through phosphorylation of BimEL at Ser-65. J Biol Chem 2006;281:25215-25222.
185. He L, Li D, Hou KZ, Liu YP. [P38 mitogen-activated protein kinase mediates glucocorticoid receptor function induced by dexamethasone in acute lymphoblastic leukemia cells]. Zhonghua Er Ke Za Zhi 2007;45:687-691.
186. Spies CM, Burmester GR, Buttgereit F. Analyses of similarities and differences in glucocorticoid therapy between rheumatoid arthritis and ankylosing spondylitis - a systematic comparison. Clin Exp Rheumatol 2009;27:S152-S158.
187. Haller J, Mikics E, Makara GB. The effects of non-genomic glucocorticoid mechanisms on bodily functions and the central neural system. A critical evaluation of findings. Front Neuroendocrinol 2008;29:273-291.
188. Reeves EK, Gordish-Dressman H, Hoffman EP, Hathout Y. Proteomic profiling of glucocorticoid-exposed myogenic cells: time series assessment of protein translocation and transcription of inactive mRNAs. Proteome Sci 2009;7:26.
189. Lowenberg M, Tuynman J, Bilderbeek J, et al. Rapid immunosuppressive effects of glucocorticoids mediated through Lck and Fyn. Blood 2005;106:1703-1710.
190. de Kloet ER, Karst H, Joels M. Corticosteroid hormones in the central stress response: quick-and-slow. Front Neuroendocrinol 2008;29:268-272.
191. Du J, Wang Y, Hunter R, et al. Dynamic regulation of mitochondrial function by glucocorticoids. Proc Natl Acad Sci USA 2009;106:3543-3548.
192. Cifone MG, Migliorati G, Parroni R, et al. Dexamethasoneinduced thymocyte apoptosis: apoptotic signal involves the sequential activation of phosphoinositide-specific phospholipase C, acidic sphingomyelinase, and caspases. Blood 1999;93:2282-2296.
193. McConkey DJ, Hartzell P, Amador-Perez JF, Orrenius S, Jondal M. Calcium-dependent killing of immature thymocytes by stimulation via the CD3/T cell receptor complex. J Immunol 1989;143:1801-1806.
194. Wang D, Muller N, McPherson KG, Reichardt HM. Glucocorticoids engage different signal transduction pathways to induce apoptosis in thymocytes and mature T cells. J Immunol 2006;176:1695-1702.
195. Lepine S, Lakatos B, Courageot MP, Le Stunff H, Sulpice JC, Giraud F. Sphingosine contributes to glucocorticoidinduced apoptosis of thymocytes independently of the mitochondrial pathway. J Immunol 2004;173:3783-3790.
196. Dowd DR, MacDonald PN, Komm BS, Haussler MR, Miesfeld R. Evidence for early induction of calmodulin gene expression in lymphocytes undergoing glucocorticoidmediated apoptosis. J Biol Chem 1991;266:18423-18426.
197. Baker A, Payne CM, Briehl MM, Powis G. Thioredoxin, a gene found overexpressed in human cancer, inhibits apoptosis in vitro and in vivo. Cancer Res 1997;57:5162-5167.
198. Tome ME, Baker AF, Powis G, Payne CM, Briehl MM. Catalase-overexpressing thymocytes are resistant to glucocorticoid-induced apoptosis and exhibit increased net tumor growth. Cancer Res 2001;61:2766-2773.
199. Hosono N, Kishi S, Iho S, et al. Glutathione S-transferase M1 inhibits dexamethasone-induced apoptosis in association with the suppression of Bim through dual mechanisms in a lymphoblastic leukemia cell line. Cancer Sci 2010;101:767-773.
200. Weber K, Bruck P, Mikes Z, Kupper JH, Klingenspor M, Wiesner RJ. Glucocorticoid hormone stimulates mitochondrial biogenesis specifically in skeletal muscle. Endocrinology 2002;143:177-184.
201. Kadowaki T, Kitagawa Y. Enhanced transcription of mitochondrial genes after growth stimulation and glucocorticoid treatment of Reuber hepatoma H-35. FEBS Lett 1988;233:51-56.
202. Rachamim N, Latter H, Malinin N, Asher C, Wald H, Garty H. Dexamethasone enhances expression of mitochondrial oxidative phosphorylation genes in rat distal colon. Am J Physiol 1995;269:C1305-C1310.
203. Psarra AM, Sekeris CE. Steroid and thyroid hormone receptors in mitochondria. IUBMB Life 2008;60:210-223.
204. Pandya JD, Agarwal NA, Katyare SS. Effect of dexamethasone treatment on oxidative energy metabolism in rat liver mitochondria during postnatal developmental periods. Drug Chem Toxicol 2004;27:389-403.
205. Demonacos C, Djordjevic-Markovic R, Tsawdaroglou N, Sekeris CE. The mitochondrion as a primary site of action of glucocorticoids: the interaction of the glucocorticoid receptor with mitochondrial DNA sequences showing partial similarity to the nuclear glucocorticoid responsive elements. J Steroid Biochem Mol Biol 1995;55:43-55.
206. Demonacos CV, Karayanni N, Hatzoglou E, Tsiriyiotis C, Spandidos DA, Sekeris CE. Mitochondrial genes as sites of primary action of steroid hormones. Steroids 1996;61:226-232.
207. Gavrilova-Jordan LP, Price TM. Actions of steroids in mitochondria. Semin Reprod Med 2007;25:154-164.
208. Scheller K, Seibel P, Sekeris CE. Glucocorticoid and thyroid hormone receptors in mitochondria of animal cells. Int Rev Cytol 2003;222:1-61.
209. Psarra AM, Hermann S, Panayotou G, Spyrou G. Interaction of mitochondrial thioredoxin with glucocorticoid receptor and NF-kappaB modulates glucocorticoid receptor and NF-kappaB signalling in HEK-293 cells. Biochem J 2009;422:521-531.
210. Hulkko SM, Zilliacus J. Functional interaction between the pro-apoptotic DAP3 and the glucocorticoid receptor. Biochem Biophys Res Commun 2002;295:749-755.
211. Fujita C, Ichikawa F, Teratani T, et al. Direct effects of corticosterone on ATP production by mitochondria from immortalized hypothalamic GT1-7 neurons. J Steroid Biochem Mol Biol 2009;117:50-55.
212. Buttgereit F, Krauss S, Brand MD. Methylprednisolone inhibits uptake of Ca2+ and Na+ ions into concanavalin A-stimulated thymocytes. Biochem J 1997;326:329-332.
213. Sionov RV, Cohen O, Kfir S, Zilberman Y, Yefenof E. Role of mitochondrial glucocorticoid receptor in glucocorticoidinduced apoptosis. J Exp Med 2006;203:189-201.
214. Talaber G, Boldizsar F, Bartis D, et al. Mitochondrial translocation of the glucocorticoid receptor in doublepositive thymocytes correlates with their sensitivity to glucocorticoid-induced apoptosis. Int Immunol 2009;21:1269-1276.
215. Adzic M, Djordjevic A, Demonacos C, Krstic-Demonacos M, Radojcic MB. The role of phosphorylated glucocorticoid receptor in mitochondrial functions and apoptotic signalling in brain tissue of stressed Wistar rats. Int J Biochem Cell Biol 2009;41:2181-2188.
216. Boopathi E, Srinivasan S, Fang JK, Avadhani NG. Bimodal protein targeting through activation of cryptic mitochondrial targeting signals by an inducible cytosolic endoprotease. Mol Cell 2008;32:32-42.
217. Nuutinen U, Ropponen A, Suoranta S, et al. Dexamethasone-induced apoptosis and up-regulation of Bim is dependent on glycogen synthase kinase-3. Leuk Res 2009;33:1714-1717.
218. Linseman DA, Butts BD, Precht TA, et al. Glycogen synthase kinase-3beta phosphorylates Bax and promotes its mitochondrial localization during neuronal apoptosis. J Neurosci 2004;24:9993-10002.
219. Pastorino JG, Hoek JB, Shulga N. Activation of glycogen synthase kinase 3beta disrupts the binding of hexokinase II to mitochondria by phosphorylating voltage-dependent anion channel and potentiates chemotherapy-induced cytotoxicity. Cancer Res 2005;65:10545-10554.
220. Sade H, Khandre NS, Mathew MK, Sarin A. The mitochondrial phase of the glucocorticoid-induced apoptotic response in thymocytes comprises sequential activation of adenine nucleotide transporter (ANT)-independent and ANT-dependent events. Eur J Immunol 2004;34:119-125.
221. Pastorino JG, Shulga N, Hoek JB. Mitochondrial binding of hexokinase II inhibits Bax-induced cytochrome c release and apoptosis. J Biol Chem 2002;277:7610-7618.
222. Tome ME, Lutz NW, Briehl MM. Overexpression of catalase or Bcl-2 alters glucose and energy metabolism concomitant with dexamethasone resistance. Biochim Biophys Acta 2004;1693:57-72.
223. Beurel E, Jope RS. The paradoxical pro- and anti-apoptotic actions of GSK3 in the intrinsic and extrinsic apoptosis signaling pathways. Prog Neurobiol 2006;79:173-189.
224. Beurel E, Michalek SM, Jope RS. Innate and adaptive immune responses regulated by glycogen synthase kinase-3 (GSK3). Trends Immunol 2010;31:24-31.
225. Rayasam GV, Tulasi VK, Sodhi R, Davis JA, Ray A. Glycogen synthase kinase 3: more than a namesake. Br J Pharmacol 2009;156:885-898.
226. Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 1995;378:785-789.
227. Goode N, Hughes K, Woodgett JR, Parker PJ. Differential regulation of glycogen synthase kinase-3 beta by protein kinase C isotypes. J Biol Chem 1992;267:16878-16882.
228. Fang X, Yu SX, Lu Y, Bast RC Jr, Woodgett JR, Mills GB. Phosphorylation and inactivation of glycogen synthase kinase 3 by protein kinase A. Proc Natl Acad Sci USA 2000;97:11960-11965.
229. Sakoda H, Gotoh Y, Katagiri H, et al. Differing roles of Akt and serum- and glucocorticoid-regulated kinase in glucose metabolism, DNA synthesis, and oncogenic activity. J Biol Chem 2003;278:25802-25807.
230. Failor KL, Desyatnikov Y, Finger LA, Firestone GL. Glucocorticoid-induced degradation of glycogen synthase kinase-3 protein is triggered by serum- and glucocorticoidinduced protein kinase and Akt signaling and controls betacatenin dynamics and tight junction formation in mammary epithelial tumor cells. Mol Endocrinol 2007;21:2403-2415.
231. Dai F, Yu L, He H, et al. Human serum and glucocorticoidinducible kinase-like kinase (SGKL) phosphorylates glycogen syntheses kinase 3 beta (GSK-3beta) at serine-9 through direct interaction. Biochem Biophys Res Commun 2002;293:1191-1196.
232. Mikosz CA, Brickley DR, Sharkey MS, Moran TW, Conzen SD. Glucocorticoid receptor-mediated protection from apoptosis is associated with induction of the serine/threonine survival kinase gene, sgk-1. J Biol Chem 2001;276:16649-16654.
233. Ding Q, Xia W, Liu JC, et al. Erk associates with and primes GSK-3beta for its inactivation resulting in upregulation of beta-catenin. Mol Cell 2005;19:159-170.
234. Zhang HH, Lipovsky AI, Dibble CC, Sahin M, Manning BD. S6K1 regulates GSK3 under conditions of mTOR-dependent feedback inhibition of Akt. Mol Cell 2006;24:185-197.
235. Hughes K, Nikolakaki E, Plyte SE, Totty NF, Woodgett JR. Modulation of the glycogen synthase kinase-3 family by tyrosine phosphorylation. EMBO J 1993;12:803-808.
236. Thomas GM, Frame S, Goedert M, Nathke I, Polakis P, Cohen P. A GSK3-binding peptide from FRAT1 selectively inhibits the GSK3-catalysed phosphorylation of axin and beta-catenin. FEBS Lett 1999;458:247-251.
237. Yost C, Farr GH 3rd, Pierce SB, Ferkey DM, Chen MM, Kimelman D. GBP, an inhibitor of GSK-3, is implicated in Xenopus development and oncogenesis. Cell 1998;93:1031-1041.
238. Bijur GN, Jope RS. Proapoptotic stimuli induce nuclear accumulation of glycogen synthase kinase-3 beta. J Biol Chem 2001;276:37436-37442.
239. Diehl JA, Cheng M, Roussel MF, Sherr CJ. Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev 1998;12:3499-3511.
240. Hoshi M, Takashima A, Noguchi K, et al. Regulation of mitochondrial pyruvate dehydrogenase activity by tau protein kinase I/glycogen synthase kinase 3beta in brain. Proc Natl Acad Sci USA 1996;93:2719-2723.
241. Bijur GN, Jope RS. Rapid accumulation of Akt in mitochondria following phosphatidylinositol 3-kinase activation. J Neurochem 2003;87:1427-1435.
242. Sotiropoulos I, Catania C, Riedemann T, et al. Glucocorticoids trigger Alzheimer disease-like pathobiochemistry in rat neuronal cells expressing human tau. J Neurochem 2008;107:385-397.
243. Smith E, Coetzee GA, Frenkel B. Glucocorticoids inhibit cell cycle progression in differentiating osteoblasts via glycogen synthase kinase-3beta. J Biol Chem 2002;277:18191-18197.
244. Wang FS, Ko JY, Weng LH, Yeh DW, Ke HJ, Wu SL. Inhibition of glycogen synthase kinase-3beta attenuates glucocorticoid-induced bone loss. Life Sci 2009;85:685-692.
245. Smith E, Frenkel B. Glucocorticoids inhibit the transcriptional activity of LEF/TCF in differentiating osteoblasts in a glycogen synthase kinase-3beta-dependent and -independent manner. J Biol Chem 2005;280:2388-2394.
246. Yun SI, Yoon HY, Jeong SY, Chung YS. Glucocorticoid induces apoptosis of osteoblast cells through the activation of glycogen synthase kinase 3beta. J Bone Miner Metab 2009;27:140-148.
247. Schmidt M, Lugering N, Lugering A, et al. Role of the CD95/CD95 ligand system in glucocorticoid-induced monocyte apoptosis. J Immunol 2001;166:1344-1351.
248. Kogianni G, Mann V, Ebetino F, et al. Fas/CD95 is associated with glucocorticoid-induced osteocyte apoptosis. Life Sci 2004;75:2879-2895.
249. Nuutinen U, Postila V, Matto M, et al. Inhibition of PI3-kinase-Akt pathway enhances dexamethasone-induced apoptosis in a human follicular lymphoma cell line. Exp Cell Res 2006;312:322-330.
250. Sade H, Krishna S, Sarin A. The anti-apoptotic effect of Notch-1 requires p56lck-dependent, Akt/PKB-mediated signaling in T cells. J Biol Chem 2004;279:2937-2944.
251. Espinosa L, Ingles-Esteve J, Aguilera C, Bigas A. Phosphorylation by glycogen synthase kinase-3 beta down-regulates Notch activity, a link for Notch and Wnt pathways. J Biol Chem 2003;278:32227-32235.
252. Miller AL, Garza AS, Johnson BH, Thompson EB. Pathway interactions between MAPKs, mTOR, PKA, and the glucocorticoid receptor in lymphoid cells. Cancer Cell Int 2007;7:3.
253. Tanaka T, Okabe T, Gondo S, et al. Modification of glucocorticoid sensitivity by MAP kinase signaling pathways in glucocorticoid-induced T-cell apoptosis. Exp Hematol 2006;34:1542-1552.
254. Dong J, Peng J, Zhang H, et al. Role of glycogen synthase kinase 3beta in rapamycin-mediated cell cycle regulation and chemosensitivity. Cancer Res 2005;65:1961-1972.
255. Yoshino T, Kishi H, Nagata T, Tsukada K, Saito S, Muraguchi A. Differential involvement of p38 MAP kinase pathway and Bax translocation in the mitochondria-mediated cell death in TCR- and dexamethasone-stimulated thymocytes. Eur J Immunol 2001;31:2702-2708.
256. Chauhan D, Pandey P, Ogata A, et al. Dexamethasone induces apoptosis of multiple myeloma cells in a JNK/SAP kinase independent mechanism. Oncogene 1997;15:837-843.
257. Druilhe A, Letuve S, Pretolani M. Glucocorticoid-induced apoptosis in human eosinophils: mechanisms of action. Apoptosis 2003;8:481-495.
258. Spokoini R, Kfir S, Yefenof E, Sionov RV. Glycogen synthase kinase 3 plays a central role in mediating glucocorticoidinduced apoptosis in multiple myeloma. 2010; In preparation.
259. De Chiara G, Marcocci ME, Torcia M, et al. Bcl-2 Phosphorylation by p38 MAPK: identification of target sites and biologic consequences. J Biol Chem 2006;281:21353-21361.
260. Pastorino JG, Hoek JB. Regulation of hexokinase binding to VDAC. J Bioenerg Biomembr 2008;40:171-182.
261. Pui CH, Evans WE. Treatment of acute lymphoblastic leukemia. N Engl J Med 2006;354:166-178.
262. Bhojwani D, Howard SC, Pui CH. High-risk childhood acute lymphoblastic leukemia. Clin Lymphoma Myeloma 2009;9(Suppl. 3):S222-S230.
263. Plasschaert SL, Kamps WA, Vellenga E, de Vries EG, de Bont ES. Prognosis in childhood and adult acute lymphoblastic leukaemia: a question of maturation? Cancer Treat Rev 2004;30:37-51.
264. Garza AS, Miller AL, Johnson BH, Thompson EB. Converting cell lines representing hematological malignancies from glucocorticoid-resistant to glucocorticoid-sensitive: signaling pathway interactions. Leuk Res 2009;33:717-727.
265. Stromberg T, Dimberg A, Hammarberg A, et al. Rapamycin sensitizes multiple myeloma cells to apoptosis induced by dexamethasone. Blood 2004;103:3138-3147.
266. Yan H, Frost P, Shi Y, et al. Mechanism by which mammalian target of rapamycin inhibitors sensitize multiple myeloma cells to dexamethasone-induced apoptosis. Cancer Res 2006;66:2305-2313.
267. Yasui H, Hideshima T, Ikeda H, et al. BIRB 796 enhances cytotoxicity triggered by bortezomib, heat shock protein (Hsp) 90 inhibitor, and dexamethasone via inhibition of p38 mitogen-activated protein kinase/Hsp27 pathway in multiple myeloma cell lines and inhibits paracrine tumour growth. Br J Haematol 2007;136:414-423.
268. Danial NN, Korsmeyer SJ. Cell death: critical control points. Cell 2004;116:205-219.
269. Chipuk JE, Moldoveanu T, Llambi F, Parsons MJ, Green DR. The BCL-2 family reunion. Mol Cell 2010;37:299-310.
270. Hartmann BL, Geley S, Loffler M, et al. Bcl-2 interferes with the execution phase, but not upstream events, in glucocorticoid-induced leukemia apoptosis. Oncogene 1999;18:713-719.
271. Memon SA, Moreno MB, Petrak D, Zacharchuk CM. Bcl-2 blocks glucocorticoid-but not Fas-or activation-induced apoptosis in a T cell hybridoma. J Immunol 1995;155:4644-4652.
272. Veis DJ, Sorenson CM, Shutter JR, Korsmeyer SJ. Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell 1993;75:229-240.
273. Holleman A, Cheok MH, den Boer ML, et al. Geneexpression patterns in drug-resistant acute lymphoblastic leukemia cells and response to treatment. N Engl J Med 2004;351:533-542.
274. Lin TS. New agents in chronic lymphocytic leukemia. Curr Hematol Malig Rep 2010;5:29-34.
275. Cheson BD. Novel therapies for peripheral T-cell non-Hodgkin's lymphomas. Curr Opin Hematol 2009;16:299-305.
276. Vogler M, Dinsdale D, Dyer MJ, Cohen GM. Bcl-2 inhibitors: small molecules with a big impact on cancer therapy. Cell Death Differ 2009;16:360-367.
277. O'Brien SM, Claxton DF, Crump M, et al. Phase I study of obatoclax mesylate (GX15-070), a small molecule pan-Bcl-2 family antagonist, in patients with advanced chronic lymphocytic leukemia. Blood 2009;113:299-305.
278. O'Brien S, Moore JO, Boyd TE, et al. Randomized phase III trial of fludarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol 2007;25:1114-1120.
279. Wang JL, Liu D, Zhang ZJ, et al. Structure-based discovery of an organic compound that binds Bcl-2 protein and induces apoptosis of tumor cells. Proc Natl Acad Sci USA 2000;97:7124-7129.
280. Becattini B, Kitada S, Leone M, et al. Rational design and real time, in-cell detection of the proapoptotic activity of a novel compound targeting Bcl-X (L). Chem Biol 2004;11:389-395.
281. Oltersdorf T, Elmore SW, Shoemaker AR, et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 2005;435:677-681.
282. Mason KD, Khaw SL, Rayeroux KC, et al. The BH3 mimetic compound, ABT-737, synergizes with a range of cytotoxic chemotherapy agents in chronic lymphocytic leukemia. Leukemia 2009;23:2034-2041.
283. Certo M, Del Gaizo Moore V, Nishino M, et al. Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer Cell 2006;9:351-365.
284. Nguyen M, Marcellus RC, Roulston A, et al. Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis. Proc Natl Acad Sci USA 2007;104:19512-19517.
285. Bonapace L, Bornhauser BC, Schmitz M, et al. Induction of autophagy-dependent necroptosis is required for childhood acute lymphoblastic leukemia cells to overcome glucocorticoid resistance. J Clin Invest 2010;120:1310-1323.
286. Maurer U, Charvet C, Wagman AS, Dejardin E, Green DR. Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1. Mol Cell 2006;21:749-760.
287. Yun SI, Yoon HY, Chung YS. Glycogen synthase kinase-3beta regulates etoposide-induced apoptosis via Bcl-2 mediated caspase-3 activation in C3H10T1/2 cells. Apoptosis 2009;14:771-777.
288. Rocha-Viegas L, Vicent GP, Baranao JL, Beato M, Pecci A. Glucocorticoids repress bcl-X expression in lymphoid cells by recruiting STAT5B to the P4 promoter. J Biol Chem 2006;281:33959-33970.
289. Viegas LR, Vicent GP, Baranao JL, Beato M, Pecci A. Steroid hormones induce bcl-X gene expression through direct activation of distal promoter P4. J Biol Chem 2004;279:9831-9839.
290. Steelman LS, Abrams SL, Whelan J, et al. Contributions of the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to leukemia. Leukemia 2008;22:686-707.
291. Trudel S, Li ZH, Wei E, et al. CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t (4;14) multiple myeloma. Blood 2005;105:2941-2948.
292. Harr MW, Caimi PF, McColl KS, et al. Inhibition of Lck enhances glucocorticoid sensitivity and apoptosis in lymphoid cell lines and in chronic lymphocytic leukemia. Cell Death Differ 2010 Mar. 19. [Epub ahead of print].
293. Sade H, Sarin A. IL-7 inhibits dexamethasone-induced apoptosis via Akt/PKB in mature, peripheral T cells. Eur J Immunol 2003;33:913-919.
294. Tsitoura DC, Rothman PB. Enhancement of MEK/ERK signaling promotes glucocorticoid resistance in CD4+ T cells. J Clin Invest 2004;113:619-627.
295. Cantley LC. The phosphoinositide 3-kinase pathway. Science 2002;296:1655-1657.
296. Liu P, Cheng H, Roberts TM, Zhao JJ. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov 2009;8:627-644.
297. Juntilla MM, Koretzky GA. Critical roles of the PI3K/Akt signaling pathway in T cell development. Immunol Lett 2008;116:104-110.
298. Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 2006;7:606-619.
299. Huang J, Manning BD. A complex interplay between Akt, TSC2 and the two mTOR complexes. Biochem Soc Trans 2009;37:217-222.
300. Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer 2002;2:489-501.
301. Jiang BH, Liu LZ. PI3K/PTEN signaling in angiogenesis and tumorigenesis. Adv Cancer Res 2009;102:19-65.
302. Martelli AM, Evangelisti C, Chiarini F, Grimaldi C, Manzoli L, McCubrey JA. Targeting the PI3K/AKT/mTOR signaling network in acute myelogenous leukemia. Expert Opin Investig Drugs 2009;18:1333-1349.
303. Silva A, Yunes JA, Cardoso BA, et al. PTEN posttranslational inactivation and hyperactivation of the PI3K/Akt pathway sustain primary T cell leukemia viability. J Clin Invest 2008;118:3762-3774.
304. Zhao WL. Targeted therapy in T-cell malignancies: dysregulation of the cellular signaling pathways. Leukemia 2010;24:13-21.
305. Gutierrez A, Sanda T, Grebliunaite R, et al. High frequency of PTEN, PI3K, and AKT abnormalities in T-cell acute lymphoblastic leukemia. Blood 2009;114:647-650.
306. Dunlop EA, Tee AR. Mammalian target of rapamycin complex 1: signalling inputs, substrates and feedback mechanisms. Cell Signal 2009;21:827-835.
307. Foster KG, Fingar DC. Mammalian target of rapamycin (mTOR): conducting the cellular signaling symphony. J Biol Chem 2010;285:14071-14077.
308. Hay N. The Akt-mTOR tango and its relevance to cancer. Cancer Cell 2005;8:179-183.
309. Leseux L, Hamdi SM, Al Saati T, et al. Syk-dependent mTOR activation in follicular lymphoma cells. Blood 2006;108:4156-4162.
310. Maddika S, Ande SR, Panigrahi S, et al. Cell survival, cell death and cell cycle pathways are interconnected: implications for cancer therapy. Drug Resist Updat 2007;10:13-29.
311. Parcellier A, Tintignac LA, Zhuravleva E, Hemmings BA. PKB and the mitochondria: AKTing on apoptosis. Cell Signal 2008;20:21-30.
312. de Frias M, Iglesias-Serret D, Cosialls AM, et al. Akt inhibitors induce apoptosis in chronic lymphocytic leukemia cells. Haematologica 2009;94:1698-1707.
313. Hideshima T, Catley L, Raje N, et al. Inhibition of Akt induces significant downregulation of survivin and cytotoxicity in human multiple myeloma cells. Br J Haematol 2007;138:783-791.
314. Grugan KD, Ma C, Singhal S, Krett NL, Rosen ST. Dual regulation of glucocorticoid-induced leucine zipper (GILZ) by the glucocorticoid receptor and the PI3-kinase/AKT pathways in multiple myeloma. J Steroid Biochem Mol Biol 2008;110:244-254.
315. Laane E, Tamm KP, Buentke E, et al. Cell death induced by dexamethasone in lymphoid leukemia is mediated through initiation of autophagy. Cell Death Differ 2009;16:1018-1029.
316. Leis H, Page A, Ramirez A, et al. Glucocorticoid receptor counteracts tumorigenic activity of Akt in skin through interference with the phosphatidylinositol 3-kinase signaling pathway. Mol Endocrinol 2004;18:303-311.
317. Chrysis D, Zaman F, Chagin AS, Takigawa M, Savendahl L. Dexamethasone induces apoptosis in proliferative chondrocytes through activation of caspases and suppression of the Akt-phosphatidylinositol 30-kinase signaling pathway. Endocrinology 2005;146:1391-1397.
318. Zhao W, Qin W, Pan J, Wu Y, Bauman WA, Cardozo C. Dependence of dexamethasone-induced Akt/FOXO1 signaling, upregulation of MAFbx, and protein catabolism upon the glucocorticoid receptor. Biochem Biophys Res Commun 2009;378:668-672.
319. Redjimi N, Gaudin F, Touboul C, et al. Identification of glucocorticoid-induced leucine zipper as a key regulator of tumor cell proliferation in epithelial ovarian cancer. Mol Cancer 2009;8:83.
320. Harms C, Albrecht K, Harms U, et al. Phosphatidylinositol 3-Akt-kinase-dependent phosphorylation of p21 (Waf1/Cip1) as a novel mechanism of neuroprotection by glucocorticoids. J Neurosci 2007;27:4562-4571.
321. Sumikawa T, Shigeoka Y, Igishi T, et al. Dexamethasone interferes with trastuzumab-induced cell growth inhibition through restoration of AKT activity in BT-474 breast cancer cells. Int J Oncol 2008;32:683-688.
322. Herr I, Buchler MW, Mattern J. Glucocorticoid-mediated apoptosis resistance of solid tumors. Results Probl Cell Differ 2009;49:191-218.
323. Hafezi-Moghadam A, Simoncini T, Yang Z, et al. Acute cardiovascular protective effects of corticosteroids are mediated by non-transcriptional activation of endothelial nitric oxide synthase. Nat Med 2002;8:473-479.
324. Limbourg FP, Huang Z, Plumier JC, et al. Rapid nontranscriptional activation of endothelial nitric oxide synthase mediates increased cerebral blood flow and stroke protection by corticosteroids. J Clin Invest 2002;110:1729-1738.
325. Teachey DT, Grupp SA, Brown VI. Mammalian target of rapamycin inhibitors and their potential role in therapy in leukaemia and other haematological malignancies. Br J Haematol 2009;145:569-580.
326. Xu Z, Wang M, Wang L, et al. Aberrant expression of TSC2 gene in the newly diagnosed acute leukemia. Leuk Res 2009;33:891-897.
327. Laplante M, Sabatini DM. mTOR signaling at a glance. J Cell Sci 2009;122:3589-3594.
328. Wang L, Harris TE, Roth RA, Lawrence JC Jr. PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding. J Biol Chem 2007;282:20036-20044.
329. Vander Haar E, Lee SI, Bandhakavi S, Griffin TJ, Kim DH. Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat Cell Biol 2007;9:316-323.
330. Sini P, James D, Chresta C, Guichard S. Simultaneous inhibition of mTORC1 and mTORC2 by mTOR kinase inhibitor AZD8055 induces autophagy and cell death in cancer cells. Autophagy 2010;6. [Epub ahead of print].
331. Wang L, Harris TE, Lawrence JC Jr. Regulation of prolinerich Akt substrate of 40 kDa (PRAS40) function by mammalian target of rapamycin complex 1 (mTORC1)-mediated phosphorylation. J Biol Chem 2008;283:15619-15627.
332. Peterson TR, Laplante M, Thoreen CC, et al. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell 2009;137:873-886.
333. Proud CG. Dynamic balancing: DEPTOR tips the scales. J Mol Cell Biol 2009;1:61-63.
334. Carriere A, Cargnello M, Julien LA, et al. Oncogenic MAPK signaling stimulates mTORC1 activity by promoting RSK-mediated raptor phosphorylation. Curr Biol 2008;18:1269-1277.
335. Gwinn DM, Shackelford DB, Egan DF, et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 2008;30:214-226.
336. Gwinn DM, Asara JM, Shaw RJ. Raptor is phosphorylated by cdc2 during mitosis. PLoS One 2010;5:e9197.
337. Huang J, Dibble CC, Matsuzaki M, Manning BD. The TSC1-TSC2 complex is required for proper activation of mTOR complex 2. Mol Cell Biol 2008;28:4104-4115.
338. Perumalsamy LR, Nagala M, Banerjee P, Sarin A. A hierarchical cascade activated by non-canonical Notch signaling and the mTOR-Rictor complex regulates neglectinduced death in mammalian cells. Cell Death Differ 2009;16:879-889.
339. Julien LA, Carriere A, Moreau J, Roux PP. mTORC1-activated S6K1 phosphorylates Rictor on threonine 1135 and regulates mTORC2 signaling. Mol Cell Biol 2010;30:908-921.
340. Treins C, Warne PH, Magnuson MA, Pende M, Downward J. Rictor is a novel target of p70 S6 kinase-1. Oncogene 2010;29:1003-1016.
341. Garcia-Martinez JM, Moran J, Clarke RG, et al. Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR). Biochem J 2009;421:29-42.
342. Guertin DA, Sabatini DM. An expanding role for mTOR in cancer. Trends Mol Med 2005;11:353-361.
343. Guertin DA, Sabatini DM. The pharmacology of mTOR inhibition. Sci Signal 2009;2:pe24.
344. Dowling RJ, Topisirovic I, Fonseca BD, Sonenberg N. Dissecting the role of mTOR: lessons from mTOR inhibitors. Biochim Biophys Acta 2010;1804:433-439.
345. Shor B, Gibbons JJ, Abraham RT, Yu K. Targeting mTOR globally in cancer: thinking beyond rapamycin. Cell Cycle 2009;8:3831-3837.
346. Yu K, Toral-Barza L, Shi C, et al. Biochemical, cellular, and in vivo activity of novel ATP-competitive and selective inhibitors of the mammalian target of rapamycin. Cancer Res 2009;69:6232-6240.
347. Yu K, Shi C, Toral-Barza L, et al. Beyond rapalog therapy: preclinical pharmacology and antitumor activity of WYE-125132, an ATP-competitive and specific inhibitor of mTORC1 and mTORC2. Cancer Res 2010;70:621-631.
348. Gu L, Gao J, Li Q, et al. Rapamycin reverses NPM-ALK-induced glucocorticoid resistance in lymphoid tumor cells by inhibiting mTOR signaling pathway, enhancing G1 cell cycle arrest and apoptosis. Leukemia 2008;22:2091-2096.
349. Cheng M, Ott GR. Anaplastic lymphoma kinase as a therapeutic target in anaplastic large cell lymphoma, nonsmall cell lung cancer and neuroblastoma. Anticancer Agents Med Chem 2010;10:236-249.
350. ten Berge RL, Meijer CJ, Dukers DF, et al. Expression levels of apoptosis-related proteins predict clinical outcome in anaplastic large cell lymphoma. Blood 2002;99:4540-4546.
351. Gascoyne RD, Aoun P, Wu D, et al. Prognostic significance of anaplastic lymphoma kinase (ALK) protein expression in adults with anaplastic large cell lymphoma. Blood 1999;93:3913-3921.
352. Savage KJ, Harris NL, Vose JM, et al. ALK-anaplastic largecell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project. Blood 2008;111:5496-5504.
353. Bai RY, Ouyang T, Miething C, Morris SW, Peschel C, Duyster J. Nucleophosmin-anaplastic lymphoma kinase associated with anaplastic large-cell lymphoma activates the phosphatidylinositol 3-kinase/Akt antiapoptotic signaling pathway. Blood 2000;96:4319-4327.
354. Gu TL, Tothova Z, Scheijen B, Griffin JD, Gilliland DG, Sternberg DW. NPM-ALK fusion kinase of anaplastic largecell lymphoma regulates survival and proliferative signaling through modulation of FOXO3a. Blood 2004;103:4622-4629.
355. Wang H, Kubica N, Ellisen LW, Jefferson LS, Kimball SR. Dexamethasone represses signaling through the mammalian target of rapamycin in muscle cells by enhancing expression of REDD1. J Biol Chem 2006;281:39128-39134.
356. DeYoung MP, Horak P, Sofer A, Sgroi D, Ellisen LW. Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling. Genes Dev 2008;22:239-251.
357. Bellot G, Garcia-Medina R, Gounon P, et al. Hypoxiainduced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains. Mol Cell Biol 2009;29:2570-2581.
358. Li Y, Wang Y, Kim E, et al. Bnip3 mediates the hypoxiainduced inhibition on mammalian target of rapamycin by interacting with Rheb. J Biol Chem 2007;282:35803-35813.
359. Sandau US, Handa RJ. Glucocorticoids exacerbate hypoxiainduced expression of the pro-apoptotic gene Bnip3 in the developing cortex. Neuroscience 2007;144:482-494.
360. Leung KT, Li KK, Sun SS, Chan PK, Ooi VE, Chiu LC. Activation of the JNK pathway promotes phosphorylation and degradation of BimEL-a novel mechanism of chemoresistance in T-cell acute lymphoblastic leukemia. Carcinogenesis 2008;29:544-551.
361. Liu J, Lin A. Role of JNK activation in apoptosis: a doubleedged sword. Cell Res 2005;15:36-42.
362. Weston CR, Davis RJ. The JNK signal transduction pathway. Curr Opin Cell Biol 2007;19:142-149.
363. Ley R, Ewings KE, Hadfield K, Cook SJ. Regulatory phosphorylation of Bim: sorting out the ERK from the JNK. Cell Death Differ 2005;12:1008-1014.
364. Putcha GV, Le S, Frank S, et al. JNK-mediated BIM phosphorylation potentiates BAX-dependent apoptosis. Neuron 2003;38:899-914.
365. Yu C, Minemoto Y, Zhang J, et al. JNK suppresses apoptosis via phosphorylation of the proapoptotic Bcl-2 family protein BAD. Mol Cell 2004;13:329-340.
366. Shaulian E, Karin M. AP-1 as a regulator of cell life and death. Nat Cell Biol 2002;4:E131-E136.
367. Hess P, Pihan G, Sawyers CL, Flavell RA, Davis RJ. Survival signaling mediated by c-Jun. NH (2)-terminal kinase in transformed B lymphoblasts. Nat Genet 2002;32:201-205.
368. Vivanco I, Palaskas N, Tran C, et al. Identification of the JNK signaling pathway as a functional target of the tumor suppressor PTEN. Cancer Cell 2007;11:555-569.
369. Zbuk KM, Eng C. Cancer phenomics: RET and PTEN as illustrative models. Nat Rev Cancer 2007;7:35-45.
370. Hashimoto A, Kurosaki M, Gotoh N, Shibuya M, Kurosaki T. Shc regulates epidermal growth factor-induced activation of the JNK signaling pathway. J Biol Chem 1999;274:20139-20143.
371. Neumann-Haefelin E, Qi W, Finkbeiner E, Walz G, Baumeister R, Hertweck M. SHC-1/p52Shc targets the insulin/IGF-1 and JNK signaling pathways to modulate life span and stress response in C. elegans. Genes Dev 2008;22:2721-2735.
372. Walk SF, March ME, Ravichandran KS. Roles of Lck, Syk and ZAP-70 tyrosine kinases in TCR-mediated phosphorylation of the adapter protein Shc. Eur J Immunol 1998;28:2265-2275.
373. Gu JJ, Ryu JR, Pendergast AM. Abl tyrosine kinases in T-cell signaling. Immunol Rev 2009;228:170-183.
374. Patrussi L, Savino MT, Pellegrini M, et al. Cooperation and selectivity of the two Grb2 binding sites of p52Shc in T-cell antigen receptor signaling to Ras family GTPases and Myc-dependent survival. Oncogene 2005;24:2218-2228.
375. Gu J, Tamura M, Pankov R, et al. Shc and FAK differentially regulate cell motility and directionality modulated by PTEN. J Cell Biol 1999;146:389-403.
376. Jin HO, Seo SK, Woo SH, et al. SP600125 negatively regulates the mammalian target of rapamycin via ATF4-induced Redd1 expression. FEBS Lett 2009;583:123-127.
377. Ishizuka T, Sakata N, Johnson GL, Gelfand EW, Terada N. Rapamycin potentiates dexamethasone-induced apoptosis and inhibits JNK activity in lymphoblastoid cells. Biochem Biophys Res Commun 1997;230:386-391.
378. Panaretakis T, Hjortsberg L, Tamm KP, Bjorklund AC, Joseph B, Grander D. Interferon alpha induces nucleusindependent apoptosis by activating extracellular signalregulated kinase 1/2 and c-Jun. NH2-terminal kinase downstream of phosphatidylinositol 3-kinase and mammalian target of rapamycin. Mol Biol Cell 2008;19:41-50.
379. Shaw RJ. LKB1 and AMP-activated protein kinase control of mTOR signalling and growth. Acta Physiol (Oxf) 2009;196:65-80.
380. Sengupta TK, Leclerc GM, Hsieh-Kinser TT, Leclerc GJ, Singh I, Barredo JC. Cytotoxic effect of 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR) on childhood acute lymphoblastic leukemia (ALL) cells: implication for targeted therapy. Mol Cancer 2007;6:46.
381. Huang X, Wullschleger S, Shpiro N, et al. Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice. Biochem J 2008;412:211-221.
382. Van Den Neste E, Van den Berghe G, Bontemps F. AICA-riboside (acadesine), an activator of AMP-activated protein kinase with potential for application in hematologic malignancies. Expert Opin Investig Drugs 2010;19:571-578.
383. Stefanelli C, Stanic I, Bonavita F, et al. Inhibition of glucocorticoid-induced apoptosis with 5-aminoimidazole-4-carboxamide ribonucleoside, a cell-permeable activator of AMP-activated protein kinase. Biochem Biophys Res Commun 1998;243:821-826.
384. Cao Y, Li H, Liu H, Zheng C, Ji H, Liu X. The serine/threonine kinase LKB1 controls thymocyte survival through regulation of AMPK activation and Bcl-XL expression. Cell Res 2010;20:99-108.
385. Christ-Crain M, Kola B, Lolli F, et al. AMP-activated protein kinase mediates glucocorticoid-induced metabolic changes: a novel mechanism in Cushing's syndrome. FASEB J 2008;22:1672-1683.
386. Palacios EH, Weiss A. Function of the Src-family kinases, Lck and Fyn, in T-cell development and activation. Oncogene 2004;23:7990-8000.
387. Lewis RS. Calcium signaling mechanisms in T lymphocytes. Annu Rev Immunol 2001;19:497-521.
388. Crabtree GR. Generic signals and specific outcomes: signaling through Ca2+, calcineurin, and NF-AT. Cell 1999;96:611-614.
389. Iwata M, Ohoka Y, Kuwata T, Asada A. Regulation of T cell apoptosis via T cell receptors and steroid receptors. Stem Cells 1996;14:632-641.
390. Jucker M, Abts H, Eick D, Lenoir GM, Tesch H. Overexpression of lck in Burkitt's lymphoma cell lines. Leukemia 1991;5:528-530.
391. Von Knethen A, Abts H, Kube D, Diehl V, Tesch H. Expression of p56lck in B-cell neoplasias. Leuk Lymphoma 1997;26:551-562.
392. Abts H, Jucker M, Diehl V, Tesch H. Human chronic lymphocytic leukemia cells regularly express mRNAs of the protooncogenes lck and c-fgr. Leuk Res 1991;15:987-997.
393. Rouer E, Dreyfus F, Melle J, Ribrag V, Benarous R. Selective increase of alternatively spliced Lck transcripts from the proximal promotor in hematopoietic malignancies. Leukemia 1993;7:246-250.
394. Majolini MB, D'Elios MM, Galieni P, et al. Expression of the T-cell-specific tyrosine kinase Lck in normal B-1 cells and in chronic lymphocytic leukemia B cells. Blood 1998;91:3390-3396.
395. Schade AE, Schieven GL, Townsend R, et al. Dasatinib, a small-molecule protein tyrosine kinase inhibitor, inhibits T-cell activation and proliferation. Blood 2008;111:1366-177.
396. Lindauer M, Hochhaus A. Dasatinib. Recent Results Cancer Res 2010;184:83-102.
397. Van Laethem F, Baus E, Smyth LA, et al. Glucocorticoids attenuate T cell receptor signaling. J Exp Med 2001;193:803-814.
398. Baus E, Andris F, Dubois PM, Urbain J, Leo O. Dexamethasone inhibits the early steps of antigen receptor signaling in activated T lymphocytes. J Immunol 1996;156:4555-4561.
399. Mansha M, Carlet M, Ploner C, et al. Functional analyses of Src-like adaptor (SLA), a glucocorticoid-regulated gene in acute lymphoblastic leukemia. Leuk Res 2010;34:529-534.
400. Jamieson CA, Yamamoto KR. Crosstalk pathway for inhibition of glucocorticoid-induced apoptosis by T cell receptor signaling. Proc Natl Acad Sci USA 2000;97:7319-7324.
401. Harada H, Quearry B, Ruiz-Vela A, Korsmeyer SJ. Survival factor-induced extracellular signal-regulated kinase phosphorylates BIM, inhibiting its association with BAX and proapoptotic activity. Proc Natl Acad Sci USA 2004;101:15313-15317.
402. Medh RD, Saeed MF, Johnson BH, Thompson EB. Resistance of human leukemic CEM-C1 cells is overcome by synergism between glucocorticoid and protein kinase A pathways: correlation with c-Myc suppression. Cancer Res 1998;58:3684-3693.
403. Thompson EB. Stepping stones in the path of glucocorticoid-driven apoptosis of lymphoid cells. Acta Biochim Biophys Sin (Shanghai) 2008;40:595-600.
404. McConkey DJ, Orrenius S, Jondal M. Agents that elevate cAMP stimulate DNA fragmentation in thymocytes. J Immunol 1990;145:1227-1230.
405. Kizaki H, Suzuki K, Tadakuma T, Ishimura Y. Adenosine receptor-mediated accumulation of cyclic AMP-induced T-lymphocyte death through internucleosomal DNA cleavage. J Biol Chem 1990;265:5280-5284.
406. Lomo J, Blomhoff HK, Beiske K, Stokke T, Smeland EB. TGF-beta 1 and cyclic AMP promote apoptosis in resting human B lymphocytes. J Immunol 1995;154:1634-1643.
407. Kiefer J, Okret S, Jondal M, McConkey DJ. Functional glucocorticoid receptor expression is required for cAMP-mediated apoptosis in a human leukemic T cell line. J Immunol 1995;155:4525-4528.
408. Ji Z, Mei FC, Miller AL, Thompson EB, Cheng X. Protein kinase A (PKA) isoform RIIbeta mediates the synergistic killing effect of cAMP and glucocorticoid in acute lymphoblastic leukemia cells. J Biol Chem 2008;283:21920-21925.
409. Refojo D, Liberman AC, Giacomini D, et al. Integrating systemic information at the molecular level: cross-talk between steroid receptors and cytokine signaling on different target cells. Ann NY Acad Sci 2003;992:196-204.
410. Ogawa R, Streiff MB, Bugayenko A, Kato GJ. Inhibition of PDE4 phosphodiesterase activity induces growth suppression, apoptosis, glucocorticoid sensitivity, p53, and p21 (WAF1/CIP1) proteins in human acute lymphoblastic leukemia cells. Blood 2002;99:3390-3397.
411. Tiwari S, Dong H, Kim EJ, Weintraub L, Epstein PM, Lerner A. Type 4 cAMP phosphodiesterase (PDE4) inhibitors augment glucocorticoid-mediated apoptosis in B cell chronic lymphocytic leukemia (B-CLL) in the absence of exogenous adenylyl cyclase stimulation. Biochem Pharmacol 2005;69:473-483.
412. Fabbro D, Manley PW. Su-6668. SUGEN. Curr Opin Investig Drugs 2001;2:1142-1148.
413. Lin B, Kolluri SK, Lin F, et al. Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3. Cell 2004;116:527-540.
414. Chauhan D, Pandey P, Hideshima T, et al. SHP2 mediates the protective effect of interleukin-6 against dexamethasoneinduced apoptosis in multiple myeloma cells. J Biol Chem 2000;275:27845-27850.
415. Chauhan D, Hideshima T, Pandey P, et al. RAFTK/PYK2-dependent and -independent apoptosis in multiple myeloma cells. Oncogene 1999;18:6733-6740.
416. Loh ML, Vattikuti S, Schubbert S, et al. Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis. Blood 2004;103:2325-2331.
417. Tartaglia M, Niemeyer CM, Fragale A, et al. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet 2003;34:148-150.
418. Tartaglia M, Niemeyer CM, Shannon KM, Loh ML. SHP-2 and myeloid malignancies. Curr Opin Hematol 2004;11:44-50.
419. Yang Z, Li Y, Yin F, Chan RJ. Activating PTPN11 mutants promote hematopoietic progenitor cell-cycle progression and survival. Exp Hematol 2008;36:1285-1296.
420. Xu R, Yu Y, Zheng S, et al. Overexpression of Shp2 tyrosine phosphatase is implicated in leukemogenesis in adult human leukemia. Blood 2005;106:3142-3149.
421. Xu R. Shp2, a novel oncogenic tyrosine phosphatase and potential therapeutic target for human leukemia. Cell Res 2007;17:295-297.
422. Matozaki T, Murata Y, Saito Y, Okazawa H, Ohnishi H. Protein tyrosine phosphatase SHP-2: a proto-oncogene product that promotes Ras activation. Cancer Sci 2009;100:1786-1793.
423. Grossmann KS, Rosario M, Birchmeier C, Birchmeier W. The tyrosine phosphatase Shp2 in development and cancer. Adv Cancer Res 2010;106:53-89.
424. Zhang SQ, Yang W, Kontaridis MI, et al. Shp2 regulates SRC family kinase activity and Ras/Erk activation by controlling Csk recruitment. Mol Cell 2004;13:341-355.
425. Radtke F, Fasnacht N, Macdonald HR. Notch signaling in the immune system. Immunity 2010;32:14-27.
426. Sandy AR, Maillard I. Notch signaling in the hematopoietic system. Expert Opin Biol Ther 2009;9:1383-1398.
427. Fortini ME. Notch signaling: the core pathway and its posttranslational regulation. Dev Cell 2009;16:633-647.
428. Aster JC, Pear WS, Blacklow SC. Notch signaling in leukemia. Annu Rev Pathol 2008;3:587-613.
429. Barrick D, Kopan R. The Notch transcription activation complex makes its move. Cell 2006;124:883-885.
430. Palomero T, Ferrando A. Therapeutic targeting of NOTCH1 signaling in T-cell acute lymphoblastic leukemia. Clin Lymphoma Myeloma 2009;9(Suppl. 3):S205-S210.
431. Tien AC, Rajan A, Bellen HJ. A Notch updated. J Cell Biol 2009;184:621-629.
432. Aifantis I, Raetz E, Buonamici S. Molecular pathogenesis of T-cell leukaemia and lymphoma. Nat Rev Immunol 2008;8:380-390.
433. Grabher C, von Boehmer H, Look AT. Notch 1 activation in the molecular pathogenesis of T-cell acute lymphoblastic leukaemia. Nat Rev Cancer 2006;6:347-359.
434. Weng AP, Ferrando AA, Lee W, et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 2004;306:269-271.
435. Sulis ML, Williams O, Palomero T, et al. NOTCH1 extracellular juxtamembrane expansion mutations in T-ALL. Blood 2008;112:733-740.
436. Lee SY, Kumano K, Masuda S, et al. Mutations of the Notch1 gene in T-cell acute lymphoblastic leukemia: analysis in adults and children. Leukemia 2005;19:1841-1843.
437. Breit S, Stanulla M, Flohr T, et al. Activating NOTCH1 mutations predict favorable early treatment response and long-term outcome in childhood precursor T-cell lymphoblastic leukemia. Blood 2006;108:1151-1157.
438. Sharma VM, Calvo JA, Draheim KM, et al. Notch1 contributes to mouse T-cell leukemia by directly inducing the expression of c-myc. Mol Cell Biol 2006;26:8022-8031.
439. Osipo C, Golde TE, Osborne BA, Miele LA. Off the beaten pathway: the complex cross talk between Notch and NF-kappaB. Lab Invest 2008;88:11-17.
440. Nefedova Y, Cheng P, Alsina M, Dalton WS, Gabrilovich DI. Involvement of Notch-1 signaling in bone marrow stroma-mediated de novo drug resistance of myeloma and other malignant lymphoid cell lines. Blood 2004;103:3503-3510.
441. Jundt F, Probsting KS, Anagnostopoulos I, et al. Jagged1-induced Notch signaling drives proliferation of multiple myeloma cells. Blood 2004;103:3511-3515.
442. Jundt F, Anagnostopoulos I, Forster R, Mathas S, Stein H, Dorken B. Activated Notch1 signaling promotes tumor cell proliferation and survival in Hodgkin and anaplastic large cell lymphoma. Blood 2002;99:3398-3403.
443. Hubmann R, Schwarzmeier JD, Shehata M, et al. Notch2 is involved in the overexpression of CD23 in B-cell chronic lymphocytic leukemia. Blood 2002;99:3742-3747.
444. Nefedova Y, Gabrilovich D. Mechanisms and clinical prospects of Notch inhibitors in the therapy of hematological malignancies. Drug Resist Updat 2008;11:210-218.
445. Morimura T, Goitsuka R, Zhang Y, Saito I, Reth M, Kitamura D. Cell cycle arrest and apoptosis induced by Notch1 in B cells. J Biol Chem 2000;275:36523-36531.
446. Romer S, Saunders U, Jack HM, Jehn BM. Notch1 enhances B-cell receptor-induced apoptosis in mature activated B cells without affecting cell cycle progression and surface IgM expression. Cell Death Differ 2003;10:833-844.
447. Zweidler-McKay PA, He Y, Xu L, et al. Notch signaling is a potent inducer of growth arrest and apoptosis in a wide range of B-cell malignancies. Blood 2005;106:3898-3906.
448. Stylianou S, Clarke RB, Brennan K. Aberrant activation of notch signaling in human breast cancer. Cancer Res 2006;66:1517-1525.
449. Pahlman S, Stockhausen MT, Fredlund E, Axelson H. Notch signaling in neuroblastoma. Semin Cancer Biol 2004;14:365-373.
450. Wang Z, Zhang Y, Li Y, Banerjee S, Liao J, Sarkar FH. Down-regulation of Notch-1 contributes to cell growth inhibition and apoptosis in pancreatic cancer cells. Mol Cancer Ther 2006;5:483-493.
451. Konishi J, Kawaguchi KS, Vo H, et al. Gamma-secretase inhibitor prevents Notch3 activation and reduces proliferation in human lung cancers. Cancer Res 2007;67:8051-8057.
452. Jehn BM, Bielke W, Pear WS, Osborne BA. Cutting edge: protective effects of notch-1 on TCR-induced apoptosis. J Immunol 1999;162:635-638.
453. Deftos ML, He YW, Ojala EW, Bevan MJ. Correlating notch signaling with thymocyte maturation. Immunity 1998;9:777-786.
454. Jang J, Choi YI, Choi J, et al. Notch1 confers thymocytes a resistance to GC-induced apoptosis through Deltex1 by blocking the recruitment of p300 to the SRG3 promoter. Cell Death Differ 2006;13:1495-1505.
455. Real PJ, Tosello V, Palomero T, et al. Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia. Nat Med 2009;15:50-58.
456. Palomero T, Sulis ML, Cortina M, et al. Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med 2007;13:1203-1210.
457. Jeon SH, Kang MG, Kim YH, et al. A new mouse gene, SRG3, related to the SWI3 of Saccharomyces cerevisiae, is required for apoptosis induced by glucocorticoids in a thymoma cell line. J Exp Med 1997;185:1827-1836.
458. Chan SM, Weng AP, Tibshirani R, Aster JC, Utz PJ. Notch signals positively regulate activity of the mTOR pathway in T-cell acute lymphoblastic leukemia. Blood 2007;110:278-286.
459. Pear WS. New roles for Notch in tuberous sclerosis. J Clin Invest 2010;120:84-87.
460. Ma J, Meng Y, Kwiatkowski DJ, et al. Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3/p63/Jagged/Notch cascade. J Clin Invest 2010;120:103-114.
461. Gutierrez A, Look AT. NOTCH and PI3K-AKT pathways intertwined. Cancer Cell 2007;12:411-413.
462. Kelly AP, Finlay DK, Hinton HJ, et al. Notch-induced T cell development requires phosphoinositide-dependent kinase 1. EMBO J 2007;26:3441-3450.
463. Mungamuri SK, Yang X, Thor AD, Somasundaram K. Survival signaling by Notch1: mammalian target of rapamycin (mTOR)-dependent inhibition of p53. Cancer Res 2006;66:4715-4724.
464. Real PJ, Ferrando AA. NOTCH inhibition and glucocorticoid therapy in T-cell acute lymphoblastic leukemia. Leukemia 2009;23:1374-1377.
465. Palomero T, Barnes KC, Real PJ, et al. CUTLL1, a novel human T-cell lymphoma cell line with t (7;9) rearrangement, aberrant NOTCH1 activation and high sensitivity to gammasecretase inhibitors. Leukemia 2006;20:1279-1287.
466. Palomero T, Lim WK, Odom DT, et al. NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth. Proc Natl Acad Sci USA 2006;103:18261-18266.
467. Tammam J, Ware C, Efferson C, et al. Down-regulation of the Notch pathway mediated by a gamma-secretase inhibitor induces anti-tumour effects in mouse models of T-cell leukaemia. Br J Pharmacol 2009;158:1183-1195.
468. Lleo A. Activity of gamma-secretase on substrates other than APP. Curr Top Med Chem 2008;8:9-16.
469. Riccio O, van Gijn ME, Bezdek AC, et al. Loss of intestinal crypt progenitor cells owing to inactivation of both Notch1 and Notch2 is accompanied by derepression of CDK inhibitors p27Kip1 and p57Kip2. EMBO Rep 2008;9:377-383.
470. O'Neil J, Grim J, Strack P, et al. FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors. J Exp Med 2007;204:1813-1824.
471. Thompson BJ, Buonamici S, Sulis ML, et al. The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia. J Exp Med 2007;204:1825-1835.
472. Gregory MA, Qi Y, Hann SR. Phosphorylation by glycogen synthase kinase-3 controls c-myc proteolysis and subnuclear localization. J Biol Chem 2003;278:51606-51612.
473. Huang M, Kamasani U, Prendergast GC. RhoB facilitates c-Myc turnover by supporting efficient nuclear accumulation of GSK-3. Oncogene 2006;25:1281-1289.
474. De Keersmaecker K, Lahortiga I, Mentens N, et al. In vitro validation of gamma-secretase inhibitors alone or in combination with other anti-cancer drugs for the treatment of T-cell acute lymphoblastic leukemia. Haematologica 2008;93:533-542.
475. Liu S, Breit S, Danckwardt S, Muckenthaler MU, Kulozik AE. Downregulation of Notch signaling by gamma-secretase inhibition can abrogate chemotherapy-induced apoptosis in T-ALL cell lines. Ann Hematol 2009;88:613-621.
476. Ausserlechner MJ, Obexer P, Bock G, Geley S, Kofler R. Cyclin D3 and c-MYC control glucocorticoid-induced cell cycle arrest but not apoptosis in lymphoblastic leukemia cells. Cell Death Differ 2004;11:165-174.
477. Yuh YS, Thompson EB. Glucocorticoid effect on oncogene/growth gene expression in human T lymphoblastic leukemic cell line CCRF-CEM. Specific c-myc mRNA suppression by dexamethasone. J Biol Chem 1989;264:10904-10910.
478. Yan M, Kuang X, Scofield VL, Shen J, Lynn WS, Wong PK. The glucocorticoid receptor is increased in Atm-/-thymocytes and in Atm-/-thymic lymphoma cells, and its nuclear translocation counteracts c-myc expression. Steroids 2007;72:415-421.
479. Moellering RE, Cornejo M, Davis TN, et al. Direct inhibition of the NOTCH transcription factor complex. Nature 2009;462:182-188.
480. Maillard I, Weng AP, Carpenter AC, et al. Mastermind critically regulates Notch-mediated lymphoid cell fate decisions. Blood 2004;104:1696-1702.
481. Oyama T, Harigaya K, Muradil A, et al. Mastermind-1 is required for Notch signal-dependent steps in lymphocyte development in vivo. Proc Natl Acad Sci USA 2007;104:9764-9769.
482. Aste-Amezaga M, Zhang N, Lineberger JE, et al. Characterization of Notch1 antibodies that inhibit signaling of both normal and mutated Notch1 receptors. PLoS One 2010;5:e9094.
483. Duma D, Jewell CM, Cidlowski JA. Multiple glucocorticoid receptor isoforms and mechanisms of post-translational modification. J Steroid Biochem Mol Biol 2006;102:11-21.
484. Lu NZ, Cidlowski JA. Translational regulatory mechanisms generate N-terminal glucocorticoid receptor isoforms with unique transcriptional target genes. Mol Cell 2005;18:331-342.
485. de Lange P, Segeren CM, Koper JW, et al. Expression in hematological malignancies of a glucocorticoid receptor splice variant that augments glucocorticoid receptormediated effects in transfected cells. Cancer Res 2001;61:3937-3941.
486. Rivers C, Levy A, Hancock J, Lightman S, Norman M. Insertion of an amino acid in the DNA-binding domain of the glucocorticoid receptor as a result of alternative splicing. J Clin Endocrinol Metab 1999;84:4283-4286.
487. Turner JD, Schote AB, Keipes M, Muller CP. A new transcript splice variant of the human glucocorticoid receptor: identification and tissue distribution of hGR Delta 313-338, an alternative exon 2 transactivation domain isoform. Ann NY Acad Sci 2007;1095:334-341.
488. Deangelo DJ, Stone RM, Silverman LB, et al. A phase I clinical trial of the notch inhibitor MK-0752 in patients with T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) and other leukemias. J Clin Oncol 2006;24;18S.