Abstract
Glucocorticosteroid hormones induce apoptosis in lymphocytes. Therefore, glucocorticoids are commonly used as immunosuppressive and chemotherapeutic agents. This review examines many facets of the process by which glucocorticoids induce apoptosis. This process is divided into three stages, an initiation stage that involves glucocorticoid receptor-mediated gene regulation, a decision stage that involves the counterbalancing influence of prosurvival and proapoptotic factors, and the execution stage which involves caspase and endonuclease activation. Many aspects of glucocorticoid-induced apoptosis, such as mitochondrial dysfunction and caspase activation, are important steps in virtually all forms of apoptosis. But the process glucocorticoid-induced apoptosis differs from other forms of apoptosis in terms of initiation at the transcriptional level and involvement of the multicatalytic proteasome and calcium. Moreover, the abundant opportunity for crosstalk between the glucocorticoid receptor and other signaling pathways increases the complexity of glucocorticoid-induced apoptosis and its regulation.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- IL:
-
interleukin
- AP-1:
-
activating protein-1
- CTLL:
-
cytotoxic T lymphocytic leukemia
- NFAT:
-
nuclear factor of activated T lymphocytes
References
Wyllie AH . 1980 Glucocorticoid-induced thymocyte apoptosis is associated with endogenous endonuclease activation Nature 284: 555–556
Helmberg A, Auphan N, Caelles C, Karin M . 1995 Glucocorticoid-induced apoptosis of human leukemic cells is caused by the repressive function of the glucocorticoid receptor EMBO J. 14: 452–460
Karin M, Liu Z-G, Zandi E . 1997 AP-1 function and regulation Curr. Opin. Cell. Biol. 9: 240–246
Wisdom R . 1999 AP-1: One switch for many signals J. Exp. Med. 253: 180–185
Walker PR, Kwast-Welfeld J, Gourdeau H, Leblanc J, Neugebauer W, Sikorska M . 1993 Relationship between apoptosis and the cell cycle in lymphocytes: roles of protein kinase C, tyrosine phosphorylation, and AP1 Exp. Cell. Res. 207: 142–151
Wisniewska M, Stanczyk M, Grzelakowska-Sztabert B, Kaminska B . 1997 Nuclear factor of activated T cells (NFAT) is a possible target for dexamethasone in thymocyte apoptosis Cell. Biol. Int. 21: 127–132
Thompson EB . 1998 The many roles of c-Myc in apoptosis Annu. Rev. Physiol. 60: 575–600
Chapman MS, Askew DJ, Kuscuoglu U, Miesfeld RL . 1996 Transcriptional control of steroid-regulated apoptosis in murine thymoma cells Mol. Endocrinol. 10: 967–978
Ramdas J, Harmon JM . 1998 Glucocorticoid-induced apoptosis and regulation of NF-kappaB activity in human leukemic T cells Endocrinology 139: 3813–3821
Reichardt HM, Kaestner KH, Tuckermann J, Katz O, Wessely O, Bock R, Gass P, Schmid W, Herrlich P, Angel P, Schutz G . 1998 DNA binding of the glucocorticoid receptor is not essential for survival Cell 93: 531–541
Kullmann M, Schneikert J, Moll J, Heck S, Zeiner M, Gehring U et al. 1998 RAP46 is a negative regulator of glucocorticoid receptor action and hormone-induced apoptosis J. Biol. Chem. 273: 14620–14625
Hulkko SM, Wakui H, Zilliacus J . 2000 The pro-apoptotic protein death-associated protein 3 (DAP3) interacts with the glucocorticoid receptor and affects the receptor function Biochem. J. 349: 885–893
Potter M, Bernstein A, Lee JM . 1998 The wst gene regulates multiple forms of thymocyte apoptosis Cell. Immunol. 188: 111–117
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
Diamond MI, Miner JN, Yoshinaga SK, Yamamoto KR . 1990 Transcription factor interactions: selectors of positive or negative regulation from a single DNA element Science 249: 1266–1272
Miner JN, Yamamoto KR . 1992 The basic region of AP-1 specifies glucocorticoid receptor activity at a composite response element Genes & Development 6: 2491–2501
Goldberg AL, Rock KL . 1992 Proteolysis, proteasomes and antigen presentation Nature 357: 375–379
Rechsteiner M, Hoffman L, Dubiel W . 1993 The multicatalytic and 26 S proteases J. Biol. Chem. 268: 6065–6068
Ciechanover A . 1994 The ubiquitin-proteasome proteolytic pathway Cell 79: 13–21
Schwartz LM, Myer A, Kosz L, Engelstein M, Maier C . 1990 Activation of polyubiquitin gene expression during developmentally programmed cell death Neuron 5: 411–419
Jones MEE, Haire MF, Kloetzel PM, Mykles DL, Schwartz LM . 1995 Changes in the structure and function of the multicatalytic proteinase (proteasome) during programmed cell death in the intersegmental muscles of the hawkmoth, Manduca sexta Develop. Biol. 169: 436–447
Dawson SP, Arnold JE, Mayer NJ, Reynolds SE, Billett MA, Gordon C, Colleaux L, Kloetzel PM, Tanaka K, Mayer RJ . 1995 Developmental changes of the 26S proteasome in abdominal intersegmental muscles of Manduca sexta during programmed cell death J. Biol. Chem. 270: 1850–1858
Lesche R, Peetz A, van der Hoeven F, Ruther U . 1997 Ft1, a novel gene related to ubiquitin-conjugating enzymes, is deleted in the Fused toes mouse mutation Mamm. Genome 8: 879–883
Grimm LM, Goldberg AL, Poirier GG, Schwartz LM, Osborne BA . 1996 Proteasomes play an essential role in thymocyte apoptosis EMBO J. 15: 3835–3844
Beyette J, Mason GG, Murray RZ, Cohen GM, Rivett AJ . 1998 Proteasome activities decrease during dexamethasone-induced apoptosis of thymocytes Biochem. J. 332: 315–320
Hirsch T, Dallaporta B, Zamzami N, Susin SA, Ravagnan L, Marzo I, Brenner C, Kroemer G . 1998 Proteasome activation occurs at an early, premitochondrial step of thymocyte apoptosis J. Immunol. 161: 35–40
Dallaporta B, Pablo M, Maisse C, Daugas E, Loeffler M, Zamzami N, Kroemer G . 2000 Proteasome activation as a critical event of thymocyte apoptosis Cell Death Differ. 7: 368–373
He H, Qi X-M, Grossman J, Distelhorst CW . 1998 c-Fos degradation by the proteasome: An early, Bcl-2 regulated step in apoptosis J. Biol. Chem. 273: 25015–25019
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
Grassilli E, Benatti F, Dansi P, Giammarioli AM, Malorni W, Franceschi C, Desiderio MA . 1998 Inhibition of proteasome function prevents thymocyte apoptosis: involvement of ornithine decarboxylase Biochem. Biophys. Res. Commun. 250: 293–297
Gil-Gomez G, Berns A, Brady HJ . 1998 A link between cell cycle and cell death: Bax and Bcl-2 modulate Cdk2 activation during thymocyte apoptosis EMBO J. 17: 7209–7218
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
Green DR . 2000 Apoptotic pathways: paper wraps stone blunts scissors Cell 102: 1–4
Di Croce L, Okret S, Kersten S, Gustafsson J, Parker M, Wahli W, Beato MS . 1999 Steroid and nuclear receptors. Villefranche-sur-Mer, France, May 25–27, 1999 EMBO J. 18: 6201–6210
Gao Y, Kinoshita Y, Hato F, Tominaga K, Tsuji Y . 1996 Suppression of glucocorticoid-induced thymocyte apoptosis by co-culture with thymic epithelial cells Cell. Mol. Biol. Noisy-le-grand 42: 227–234
Ferlin-Bezombes M, Jourdan M, Liautard J, Brochier J, Rossi JF, Klein B . 1998 IFN-alpha is a survival factor for human myeloma cells and reduces dexamethasone-induced apoptosis J. Immunol. 161: 2692–2699
Chauhan D, Pandey P, Ogata A, Teoh G, Treon S, Urashima M, Kharbanda S, Anderson KC . 1997 Dexamethasone induces apoptosis of multiple myeloma cells in a JNK/SAP kinase independent mechanism Oncogene 15: 837–843
Xu FH, Sharma S, Gardner A, Tu Y, Raitano A, Sawyers C, Lichtenstein A . 1998 Interleukin-6-induced inhibition of multiple myeloma cell apoptosis: support for the hypothesis that protection is mediated via inhibition of the JNK/SAPK pathway Blood 92: 241–251
Van Snick J, Houssiau F, Proost P, Van Damme J, Renauld JC . 1996 I-309/T cell activation gene-3 chemokine protects murine T cell lymphomas against dexamethasone-induced apoptosis J. Immunol. 157: 2570–2576
Bauer JH, Liu KD, You Y, Lai SY, Goldsmith MA . 1998 Heteromerization of the gammac chain with the interleukin-9 receptor alpha subunit leads to STAT activation and prevention of apoptosis J. Biol. Chem. 273: 9255–9260
Bulfone-Paus S, Ungureanu D, Pohl T, Lindner G, Paus R, Ruckert R, Krause H, Kunzendorf U . 1997 Interleukin-15 protects from lethal apoptosis in vivo Nat. Med. 3: 1124–1128
Xu F, Gardner A, Tu Y, Michl P, Prager D, Lichtenstein A . 1997 Multiple myeloma cells are protected against dexamethasone-induced apoptosis by insulin-like growth factors Br. J. Haematol. 97: 429–440
Guizani L, Perrin-Wolff M, Breard J, Binetruy B, Bertoglio J . 1996 Mechanisms in interleukin-2 protection against glucocorticoid-induced apoptosis: regulation of AP-1 and glucocorticoid receptor transcriptional activities J. Interferon Cytokine Res. 16: 601–609
Ogawa M, Nishiura T, Oritani K, Yoshida H, Yoshimura M, Okajima Y, Ishikawa J, Hashimoto I, Matsumura I, Tomiyama Y, Matsuzawa Y . 2000 Cytokines prevent dexamethasone-induced apoptosis via the activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways in a new multiple myeloma cell line Cancer Res. 60: 4262–4269
Wang W, Wykrzykowska J, Johnson T, Sen R, Sen J . 1999 A NF-kappa B/c-myc-dependent survival pathway is targeted by corticosteroids in immature thymocytes J. Immunol. 162: 314–322
Xie H, Seward RJ, Huber BT . 1997 Cytokine rescue from glucocorticoid induced apoptosis in T cells is mediated through inhibition of IkappaBalpha Mol. Immunol. 34: 987–994
Auphan N, DiDonato JA, Rosette C, Helmberg A, Karin M . 1995 Immunosuppression of I kappa B synthesis [see comments] Science 270: 286–290
Brostjan C, Anrather J, Csizmadia V, Stroka D, Soares M, Bach FH et al. 1996 Glucocorticoid-mediated repression of NFkB activity in endothelial cells does not involve induction of IkBa synthesis J. Biol. Chem. 271: 19612–19616
De Bosscher K, Schmitz ML, Vanden Berghe W, Plaisance S, Fiers W, Haegeman G . 1997 Glucocorticoid-mediated repression of nuclear factor-kB-dependent transcription involves direct interference with transactivation Proc. Natl. Acad. Sci. USA 94: 13504–13509
Heck S, Bender K, Kullmann M, Gottlicher M, Herrlich P, Cato AC . 1997 I kappaB alpha-independent downregulation of NF-kappaB activity by glucocorticoid receptor EMBO J. 16: 4698–4707
Adcock IM, Nasuhara Y, Stevens DA, Barnes PJ . 1999 Ligand-induced differentiation of glucocorticoid receptor (GR) trans-repression and transactivation: preferential targeting of NF-kappaB and lack of I-kappaB involvement Br. J. Pharmacol. 127: 1003–1011
Asada A, Zhao Y, Kondo S, Iwata M . 1998 Induction of thymocyte apoptosis by Ca2+-independent protein kinase C (nPKC) activation and its regulation by calcineurin activation J. Biol. Chem. 273: 28392–28398
Stefanelli C, Stanic I, Bonavita F, Flamigni F, Pignatti C, Guarnieri C, Caldarera CM . 1998 Inhibition of glucocorticoid-induced apoptosis with 5-aminoimidazole-4-carboxamide ribonucleoside, a cell-permeable activator of AMP-activated protein kinase Biochem. Biophys. Res. Commun. 243: 821–826
Walach D, Varfolomeev E, Malinin N, Goltsev Y, Kovalenko A, Boldin M . 1999 Tumor necrosis factor receptor and Fas signaling mechanisms Annu. Rev. Immunol. 17: 331–367
Jamieson CA, Yamamoto KR . 2000 Crosstalk pathway for inhibition of glucocorticoid-induced apoptosis by T cell receptor signaling [In Process Citation] Proc. Natl. Acad. Sci. USA 97: 7319–7324
Sears R, Leone G, DeGregori J, Nevins JR . 1999 Ras enhances Myc protein stability Mol. Cell 3: 169–179
Wakui H, Wright AP, Gustafsson J, Zilliacus J . 1997 Interaction of the ligand-activated glucocorticoid receptor with the 14-3-3 eta protein J. Biol. Chem. 272: 8153–8156
Widen C, Zilliacus J, Gustafsson JA, Wikstrom AC . 2000 Glucocorticoid receptor Interaction with 14-3-3 and Raf-1, a proposed mechanism for crosstalk of two signal transduction pathways J. Biol. Chem
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
Bian X, Hughes FM, Huang Y, Cidlowski JA, Putney JW . 1997 Roles of cytoplasmic Ca2+ and intracellular Ca2+ stores in induction and suppression of apoptosis in S49 cells Am. J. Physiol. 272 (Cell Physiol. 41): C1241–C1249
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 Bcl-2 regulated caspase activation Mol. Cell. Endocrin. 139: 229–238
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
Gross A, McDonnell JM, Korsmeyer SJ . 1999 BCL-2 family members and the mitochondria in apoptosis Genes Dev. 13: 1899–1911
Kroemer G, Reed JC . 2000 Mitochondrial control of cell death Nature Medicine 6: 513–519
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
Hakem A, Sasaki T, Kozieradzki I, Penninger JM . 1999 The cyclin-dependent kinase Cdk2 regulates thymocyte apoptosis J. Exp. Med. 189: 957–967
Feinman R, Koury J, Thames M, Barlogie B, Epstein J, Siegel DS . 1999 Role of NF-kappaB in the rescue of multiple myeloma cells from glucocorticoid-induced apoptosis by bcl-2 Blood 93: 3044–3052
Budijardjo I, Oliver H, Lutter M, Luo X, Wang X . 1999 Biochemical pathways of caspase activation during apoptosis Annu. Rev. Cell. Dev. Biol. 15: 269–290
Wang HG, Pathan N, Ethell IM, Krajewski S, Yamaguchi Y, Shibasaki F . 1999 Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD Science 284: 339–343
Holinger EP, Chittenden T, Lutz RJ . 1999 Bak BH3 peptides antagonize Bcl-xL function and induce apoptosis through cytochrome c-independent activation of caspases J. Biol. Chem. 274: 13298–13304
Yin XM, Wang K, Gross A, Zhao Y, Zinkel S, Klocke B, Roth KA, Korsmeyer SJ . 1999 Bid-deficient mice are resistant to Fas-induced hepatocellular apoptosis Nature 400: 886–891
Knudson CM, Tung KS, Tourtellotte WG, Brown GA, Korsmeyer SJ . 1995 Bax-deficient mice with lymphoid hyperplasia and male germ cell death Science 270: 96–99
Hsu YT, Wolter KG, Youle RJ . 1997 Cytosol-to-membrane redistribution of Bax and Bcl-X(L) during apoptosis Proc. Natl. Acad. Sci. USA 94: 3668–3672
Griffiths GJ, Dubrez L, Morgan CP, Jones NA, Whitehouse J, Corfe BM et al. 1999 Cell damage-induced conformational changes of the pro-apoptotic protein Bak in vivo precede the onset of apoptosis J. Cell. Biol. 144: 903–914
Thomson JM, Waldrip HW, Compton MM . 1997 Identification of a differential display product associated with apoptosis in chicken thymocytes Dev. Comp. Immunol. 21: 413–424
Mok CL, Gil-Gomez G, Williams O, Coles M, Taga S, Tolaini M, Norton T, Kioussis D, Brady HJ . 1999 Bad can act as a key regulator of T cell apoptosis and T cell development J. Exp. Med. 189: 575–586
Bouillet P, Metcalf D, Huang DC, Tarlinton DM, Kay TW, Kontgen F, Adams JM, Strasser A . 1999 Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity Science 286: 1735–1738
Orrenius S, McConkey DJ, Nicotera P . 1991 Role of calcium in toxic and programmed cell death Adv. Exp. Med. Biol. 283: 419–425
Distelhorst CW, Dubyak G . 1998 Role of calcium in glucocorticosteroid-induced apoptosis of thymocytes and lymphoma cells: Resurrection of old theories by new findings Blood 91: 731–734
Squier MK, Cohen JJ . 1997 Calpain, an upstream regulator of thymocyte apoptosis J. Immunol. 158: 3690–3697
Lam M, Dubyak G, Distelhorst CW . 1993 Effect of glucocorticosteroid treatment on intracellular calcium homeostasis in mouse lymphoma cells Mol. Endocrinol. 7: 686–693
Hughes FM Jr, Bortner CD, Purdy GD, Cidlowski JA . 1997 Intracellular K+ suppresses the activation of apoptosis in lymphocytes J. Biol. Chem. 272: 30567–30576
Khan AA, Soloski MJ, Sharp AH, Schilling G, Sabatini DM, Li S-H, Ross CA, Snyder SH . 1996 Lymphocyte apoptosis: Mediation by increased type 3 inositol 1,4,5-trisphosphate receptor Science 273: 503–507
Jayaraman T, Marks AR . 1997 T cells deficient in inositol 1,4,5-trisphosphate receptor are resistant to apoptosis Mol. Cell. Biol. 17: 3005–3012
Chvatchko Y, Valera S, Aubry J-P, Renno T, Buell G, Bonnefoy J-Y . 1996 The involvement of an ATP-gated ion channel, P2X1, in thymocyte apoptosis Immunity 5: 275–283
Jiang S, Kull B, Fredholm BB, Orrenius S . 1996 P2x purinoceptor is not important in thymocyte apoptosis Immunol. Lett. 49: 197–201
Bortner CD, Cidlowski JA . 2000 Volume regulation and ion transport during apoptosis [In Process Citation] Methods Enzymol. 322: 421–433
Benson RS, Heer S, Dive C, Watson AJ . 1996 Characterization of cell volume loss in CEM-C7A cells during dexamethasone-induced apoptosis Am. J. Physiol. 270: 1190–1203
Bortner C, Hughes FM Jr, Cidlowski JA . 1997 A primary role for K+ and Na+ efflux in the activation of apoptosis J. Biol. Chem. 272: 32436–32442
Dallaporta B, Marchetti P, de Pablo MA, Maisse C, Duc HT, Metivier D et al. 1999 Plasma membrane potential in thymocyte apoptosis J. Immunol. 162: 6534–6542
Kolesnick RN, Kronke M . 1998 Regulation of ceramide production and apoptosis Annu. Rev. Physiol. 60: 643–665
Green DR . 2000 Apoptosis and sphingomyelin hydrolysis. The flip side [comment] J. Cell. Biol. 150: F5–7
Cifone MG, Migliorati G, Parroni R, Marchetti C, Millimaggi D, Santoni A, Tepper AD, Ruurs P, Weidmer T, Sims PJ, Borst J, van Blitterswijk WJ . 1999 Dexamethasone-induced thymocyte apoptosis: apoptotic signal involves the sequential activation of phosphoinositide-specific phospholipase C, acidic sphingomyelinase, and caspases Blood 93: 2282–2296
Tepper AD, Ruurs P, Wiedmer T, Sims PJ, Borst J, van Blitterswijk WJ . 2000 Sphingomyelin hydrolysis to ceramide during the execution phase of apoptosis results from phospholipid scrambling and alters cell-surface morphology [see comments] J. Cell. Biol. 150: 155–164
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
Yoshida H, Kong YY, Yoshida R, Elia AJ, Hakem A, Hakem R, Duncan GS, Henderson JT, Woo M, Soengas MS, Elia A, de la Pompa JL, Kagi D, Khoo W, Potter J, Yoshida R, Kaufman SA, Lowe SW, Penninger JM, Mak TW . 1998 Apaf1 is required for mitochondrial pathways of apoptosis and brain development Cell 94: 739–750
Hakem R, Hakem A, Duncan GS, Henderson JT, Woo M, Soengas MS, Kuida K, Haydar TF, Kuan CY, Gu Y, Taya C, Karasuyama H, Su MS, Rakic P, Flavell RA . 1998 Differential requirement for caspase 9 in apoptotic pathways in vivo Cell 94: 339–352
Kuida K, Haydar TF, Kuan CY, Gu Y, Taya C, Karasuyama H, Li P, Allen H, Banerjee S, Seshadri T . 1998 Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9 Cell 94: 325–337
Li P, Allen H, Banerjee S, Seshadri T . 1997 Characterization of mice deficient in interleukin-1 beta converting enzyme J. Cell. Biochem. 64: 27–32
Kuida K, Zheng TS, Na S, Kuan C-y, Yang D, Karasuyama H, Sarin A, Wu ML, Henkart PA . 1996 Decreased apoptosis in the brain and premature lethality in CP32-deficient mice Nature 384: 368–372
Sarin A, Wu ML, Henkart PA . 1996 Different interleukin-1 beta converting enzyme (ICE) family protease requirements for the apoptotic death of T lymphocytes triggered by diverse stimuli J. Exp. Med. 184: 2445–2450
Bellosillo B, Dalmau M, Colomer D, Gil J . 1997 Involvement of CED-3/ICE proteases in the apoptosis of B-chronic lymphocytic leukemia cells Blood 89: 3378–3384
Hughes FM Jr, Cidlowski JA . 1998 Glucocorticoid-induced thymocyte apoptosis: protease-dependent activation of cell shrinkage and DNA degradation J. Steroid Biochem. Mol. Biol. 65: 207–217
Weimann E, Baixeras E, Zamzami N, Kelly P . 1999 Prolactin blocks glucocorticoid induced cell death by inhibiting the disruption of the mitochondrial membrane Leuk Res. 23: 751–762
Robertson NM, Zangrilli J, Fernandes-Alnemri T, Friesen PD, Litwak G, Alnemri ES . 1997 Baculovirus p35 inhibits the glucocorticoid-mediated pathway of cell death Cancer Res. 57: 43–47
Miyashita T, Nagao K, Krajewski S, Salvesen GS, Reed JC, Inoue T, Alam A, Braun MY, Hartgers F, Lesage S, Cohen L, Hugo P, Denis F, Sekaly RP . 1998 Investigation of glucocorticoid-induced apoptotic pathway: processing of caspase-6 but not caspase-3 Cell Death Differ. 5: 1034–1041
Alam A, Braun MY, Hartgers F, Lesage S, Cohen L, Hugo P, Komoriya A, Packard BZ, Brown MJ, Wu M-L, Henkart PA . 1997 Specific activation of the cysteine protease CPP32 during the negative selection of T cells in the thymus J. Exp. Med. 186: 1503–1512
Komoriya A, Packard BZ, Brown MJ, Wu M-L, Henkart PA . 2000 Assessment of caspase activities in intact apoptotic thymocytes using cell-permeable fluorogenic caspase substrates J. Exp. Med. 191: 1819–1828
Castedo M, Macho A, Zamzami N, Hirsch T, Marchetti P, Uriel J, Susin SA, Zamzami N, Marchetti P, Macho A, Kroemer G . 1995 Mitochondrial perturbations define lymphocytes undergoing apoptotic depletion in vivo Eur. J. Immunol. 25: 3277–3284
Castedo M, Hirsch T, Susin ZA, Zamzami N, Marchetti P, Macho A, Chauhan D, Pandey P, Ogata A, Teoh G, Krett N, Halgren R, Rosen S, Kufe D, Anderson K . 1996 Sequential acquisition of mitochondrial and plasma membrane alterations during early lymphocyte apoptosis J. Immunol. 157: 512–521
Chauhan D, Pandey P, Ogata A, Teoh G, Krett N, Halgren R, Gaynon PS, Carrel AL . 1997 Cytochrome c-dependent and -independent induction of apoptosis in multiple myeloma cells J. Biol. Chem. 272: 29995–29997
Gaynon PS, Carrel AL . 1999 Glucocorticosteroid therapy in childhood acute lymphoblastic leukemia Adv. Exp. Med. Biol. 457: 593–605
Kaspers GJ, Pieters R, Van Zantwijk CH, Van Wering ER, Van Der Does-Van Den Berg A, Veerman AJ . 1998 Prednisolone resistance in childhood acute lymphoblastic leukemia: vitro-vivo correlations and cross-resistance to other drugs Blood 92: 259–266
Hillmann AG, Ramdas J, Multanen K, Norman MR, Harmon JM . 2000 Glucocorticoid receptor gene mutations in leukemic cells acquired in vitro and in vivo Cancer Res. 60: 2056–2062
Lubbert M, Mirro J, Miller CW, Kahan J, Isaac G, Salomons GS, Brady HJ, Verwijs-Janssen M, Van Den Berg JD, Hart AA, Van Den Berg H, Behrendt H, Hahlen K, Smets LA . 1990 N-ras gene point mutations in childhood acute lymphocytic leukemia correlate with a poor prognosis Blood 75: 1163–1169
Salomons GS, Brady HJ, Verwijs-Janssen M, Van Den Berg JD, Hart AA, Van Den Berg H . 1997 The Bax alpha:Bcl-2 ratio modulates the response to dexamethasone in leukaemic cells and is highly variable in childhood acute leukaemia Int. J. Cancer 71: 959–965
Salomons GS, Smets LA, Verwijs-Janssen M, Hart AA, Haarman EG, Kaspers GJ, Pieters R, van Zantwijk CH, Broekema GJ, Hahlen K, Veerman AJ . 1999 Bcl-2 family members in childhood acute lymphoblastic leukemia: relationships with features at presentation, in vitro and in vivo drug response and long-term clinical outcome Leukemia 13: 1574–1580
Haarman EG, Kaspers GJ, Pieters R, van Zantwijk CH, Broekema GJ, Hahlen K, Veerman AJ . 1999 BCL-2 expression in childhood leukemia versus spontaneous apoptosis, drug induced apoptosis, and in vitro drug resistance Adv. Exp. Med. Biol. 457: 325–333
Acknowledgements
This work was supported by NIH grant CA42755.
Author information
Authors and Affiliations
Corresponding author
Additional information
Edited by G Nunez
Rights and permissions
About this article
Cite this article
Distelhorst, C. Recent insights into the mechanism of glucocorticosteroid-induced apoptosis. Cell Death Differ 9, 6–19 (2002). https://doi.org/10.1038/sj.cdd.4400969
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/sj.cdd.4400969
Keywords
This article is cited by
-
Chronic stress decreases ornithine decarboxylase expression and protects against 1,2-dimethylhydrazine-induced colon carcinogenesis
Molecular Biology Reports (2020)
-
Metabolic reprogramming of acute lymphoblastic leukemia cells in response to glucocorticoid treatment
Cell Death & Disease (2018)
-
Mechanism of inhibition of Shiga-toxigenic Escherichia coli SubAB cytotoxicity by steroids and diacylglycerol analogues
Cell Death Discovery (2018)
-
Subchronic Glucocorticoid Receptor Inhibition Rescues Early Episodic Memory and Synaptic Plasticity Deficits in a Mouse Model of Alzheimer’s Disease
Neuropsychopharmacology (2015)
-
Paclitaxel-induced transcriptional regulation of Fas signaling pathway is antagonized by dexamethasone
Breast Cancer Research and Treatment (2015)


