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Recent Insights Into the Mechanism of Glucocorticosteroid- Induced Apoptosis

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Recent Insights Into the Mechanism of Glucocorticosteroid- Induced Apoptosis Cell Death and Differentiation (2002) 9, 6±19 ã 2002 Nature Publishing Group All rights reserved 1350-9047/02 $25.00 www.nature.com/cdd Review Recent insights into the mechanism of glucocorticosteroid- induced apoptosis CW Distelhorst*,1 apoptosis.1 But progress in understanding corticosteroid- induced apoptosis has lagged behind remarkable advances in 1 Division of Hematology/Oncology and Comprehensive Cancer Center, understanding other forms of apoptosis, such as that induced Departments of Medicine and Pharmacology, Case Western Reserve by the ligands of death receptors (e.g., Fas/CD95, tumor University School of Medicine and University Hospitals of Cleveland, necrosis factor). In part, this is because corticosteroid-induced Cleveland, Ohio, USA apoptosis is initiated by a steroid receptor-mediated change in * Corresponding author: CW Distelhorst, Division of Hematology/Oncology, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio, gene expression, but specific genes that mediate cell death in OH 44106-4937, USA. Tel: 216-368-1175; Fax: 216-368-1166; response to corticosteroid treatment have not been identified. E-mail: [email protected] Recent findings have shed light on events in the cell death pathway downstream from gene regulation, including the Received 20.7.01; revised 7.9.01; accepted 3.10.01 caspases responsible for the execution phase of cell death, Edited by G Nunez the unexpected involvement of the multicatalytic proteasome in the death process, the suppression of prosurvival transcrip- tion factors (e.g., AP-1, c-myc,NF-kB), and crosstalk between Abstract T cell receptor and cytokine signaling pathways. Moreover, Glucocorticosteroid hormones induce apoptosis in lympho- evidence that mitochondrial dysfunction lies downstream of cytes. Therefore, glucocorticoids are commonly used as caspase activation in corticosteroid-induced apoptosis chal- immunosuppressive and chemotherapeutic agents. This lenges the generalization that mitochondrial dysfunction is the review examines many facets of the process by which central decision point in all forms of apoptosis. glucocorticoids induce apoptosis. This process is divided This review focuses primarily on insights gained in recent years regarding the mechanism of corticosteroid-induced into three stages, an initiation stage that involves glucocorti- apoptosis. Ultimately, the goal of investigating this form of coid receptor-mediated gene regulation, a decision stage that apoptosis is to better understand the role of corticosteroid involves the counterbalancing influence of prosurvival and hormones in physiological regulation of the immune system proapoptotic factors, and the execution stage which involves and in the treatment of lymphoid leukemias and lymphomas. caspase and endonuclease activation. Many aspects of To organize this review, corticosteroid-induced apoptosis glucocorticoid-induced apoptosis, such as mitochondrial is arbitrarily divided into three stages: the initiation stage, the dysfunction and caspase activation, are important steps in decision stage, and the execution stage (Figure 1). The virtually all forms of apoptosis. But the process glucocorti- initiation stage involves corticosteroid receptor-mediated coid-induced apoptosis differs from other forms of apoptosis changes in gene expression, while the execution stage in terms of initiation at the transcriptional level and involves activation of caspases, or other proteases and involvement of the multicatalytic proteasome and calcium. endonucleases. The decision stage includes those events that ultimately result in a commitment to cell death. A decision Moreover, the abundant opportunity for crosstalk between the to die appears to be made by counterbalancing actions of glucocorticoid receptor and other signaling pathways cytokines, which induce transcription factors that promote cell increases the complexity of glucocorticoid-induced apopto- proliferation and survival, versus the actions of corticoster- sis and its regulation. oids, which oppose the expression of these transcription Cell Death and Differentiation (2002) 9, 6 ± 19. DOI: 10.1038/sj/ factors. An important feature of corticosteroid-induced cdd/4400969 apoptosis is involvement of the multicatalytic proteasome, which appears to play an active role in promoting cell death by Keywords: glucocorticosteroid; dexamethasone; apoptosis; leu- degrading factors necessary for cell survival. kemia; lymphoma Abbreviations: IL, interleukin; AP-1, activating protein-1; CTLL, The initiation stage cytotoxic T lymphocytic leukemia; NFAT, nuclear factor of activated Glucocorticoid receptor mediated changes in gene T lymphocytes transcription In this review, the initiation stage is defined as the sequence of events leading up to and including direct regulation of gene Introduction transcription by the corticosteroid receptor (Figure 2). But The induction of apoptosis in thymocytes by glucocorticoster- what genes are regulated so that the lymphoid cell ultimately oid hormones is one of the earliest recognized forms of dies? The answer to this question has evaded investigators Glucocorticoid-induced apoptosis CW Distelhorst 7 Figure 1 Stages of glucocorticoid-induced apoptosis. Between the Initiation Stage and the Execution Stage lies the Decision Stage in which counterbalancing factors determine the commitment of the cell to live or die. Recent findings indicate that repression of prosurvival transcription factors and proteasome-mediated degradation of apoptosis inhibitory factors may play a crucial role in this stage genes involved in cell growth, differentiation and transforma- tion,3,4 their findings suggested that interference with transcription factors required for cell survival, such as AP-1 (activating protein-1), may contribute to apoptosis induction.2 This interpretation is consistent with earlier findings indicating that in cytokine (IL-2)-dependent CTLL cells there is a correlation between the presence of AP-1 DNA binding activity and repression of corticosteroid-induced apoptosis.5 In the absence of interleukin-2, corticosteroid treatment stimulates AP-1 degradation and induces apoptosis.5 The repression of AP-1 transcription factor activity in Figure 2 The Initiation Stage. There is considerable evidence that corticosteroid-treated lymphocytes is accompanied by glucocorticoid-induced apoptosis is initiated by the transactivation activity of the glucocorticoid receptor, but the specific genes regulated in this process repression of other prosurvival transcription factors, includ- 6 are not yet identified. RAP46/BAG1 represses the transactivation activity of ing the nuclear factor of activated T lymphocytes (NFAT). the glucocorticoid receptor, and therefore inhibits glucocorticoid-induced NFAT is composed of two components, NFATp and AP-1; apoptosis. Glucocorticoid-induced apoptosis is also repressed by T cell the dexamethasone-induced decrease in NFAT activity is receptor (TCR) signaling, which appears to alter the transactivation activity of due to a decrease in AP-1 activity.6 Also, Thompson and the glucocorticoid receptor. On the other hand, DAP3 increases glucocorti- 7 coid-induced apoptosis by enhancing the transactivation activity of the coworkers have provided substantial evidence that down- glucocorticoid receptor regulation of c-Myc accompanies the induction of apoptosis by corticosteroids, and that c-Myc overexpression inhibits corticosteroid-induced apoptosis. up to the present time. In part, the difficulty has been knowing what to look for: the induction of a gene or set of genes that produce cell death as a direct or indirect consequence of their Evidence for involvement of the glucocorticoid biological action, or the repression of genes necessary for receptor transactivation activity in maintenance of cell survival, or a combination of both? One glucocorticoid-induced apoptosis specific point of confusion in understanding corticosteroid- Recent evidence from several laboratories indicates that the induced apoptosis has to do with whether the transactivation transactivation activity of the glucocorticoid receptor is or transrepression functions of the corticosteroid receptor required to mediate corticosteroid-induced apoptosis. Chap- initiate the process of cell death. Evidence in favor of each is man et al 8 found that chimeric receptors containing the potent summarized here. VP16 and E1A viral transactivation domains in place of the corticosteroid receptor amino terminus enhanced the sensi- tivity of lymphoid cells to corticosteroid-induced apoptosis, Evidence for involvement of the glucocorticoid supporting a role for transactivation in apoptosis induction. receptor transrepression activity in Ramdas et al 9 addressed the question by comparing human glucocorticoid-induced apoptosis leukemic T cells that express either wild type corticosteroid The concept that corticosteroid-induced apoptosis is receptor or receptor that has a mutation that is activation mediated by the transrepression activity of the glucocorticoid deficient, but that retains the ability to repress AP-1 activity. receptor was largely based on the work of Helmberg et al.2 This mutant failed to mediate corticosteroid-induced apopto- These investigators reported that mutant glucocorticoid sis, indicating that the transactivation function of the receptor receptors defective in transactivation function, but fully is essential for corticosteroid-induced apoptosis. In a similar competent at interfering with AP-1 (activating protein-1) approach in vivo,
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