Using Gene Expression Profiling to Understand the Mechanism of Glucocorticoid-Induced Apoptosis in Lymphoid Malignancies
Glucocorticoids are essential for the successful treatment of many types of leukemia and lymphoma. The efficacy of glucocorticoids stems from their ability to induce apoptosis in immature lymphocytes, a process that requires the de novo transcription of genes. However, the glucocorticoid-regulated genes that initiate the apoptotic program are not known. Because identification of these genes is essential to developing more effective and less toxic therapies for lymphoid malignancies, we used gene expression profiling to identify glucocorticoid-regulated transcripts that potentially contribute to the apoptotic response. In lymphoma cell lines and primary thymocytes, the synthetic glucocorticoid dexamethasone induced the expression of Bim, a pro-apoptotic member of the Bcl-2 family of apoptosis regulatory proteins. The induction of Bim protein is closely followed by the induction of apoptosis, suggesting that it is a key initiator of the apoptotic program. Surprisingly, dexamethasone did not regulate the transcription of members of the apoptotic machinery other than Bim. Dexamethasone also markedly induced expression of the G protein-coupled receptor TDAG8. Activation of TDAG8 significantly enhanced glucocorticoid-induced apoptosis, suggesting that its agonists it may be promising adjuvants to increase the efficacy or reduce the adverse effects associated with glucocorticoid therapy. In addition to Bim and TDAG8, dexamethasone regulated the expression of genes that antagonize proliferation and survival signals. These data support the hypothesis that the process of glucocorticoid-induced apoptosis involves multiple signal transduction pathways, each acting in concert to convince the lymphocyte to die. This work has identified several of such pathways that may be viable targets for improved chemotherapeutics to treat lymphoid malignancies.
School:Case Western Reserve University
School Location:USA - Ohio
Source Type:Master's Thesis
Keywords:apoptosis glucocorticoids g protein coupled receptors gene expression microarray leukemia lymphoma
Date of Publication:01/01/2005