The long-term goal of this ongoing grant is understanding how the glucocorticoid receptor (GR) regulates genes to effect the death of leukemic lymphoid cells. Our findings have laid the groundwork for research in our next grant period. Glucocorticoids, through activation of the GR, have identified several landmark genes whose regulation by glucocorticoids precedes the onset of overt apoptosis. Of high significance is the observation that transcriptional repression of c-myc is invariably seen in cells sensitive to glucocorticoid (or rendered sensitive by activation of protein kinase A). We have begun gene array analysis to reveal all such genes antecedent to the eventual apoptotic events. We have developed a well-controlled set of clonal cell lines from the human acute lymphoblastic leukemia CEM cell line. Comparing the genes expressed in these clones will allow us to identify the genes whose regulation is specifically relevant to apoptotic onset. Our recent discovery of two pharmacological interventions that enhance glucocorticoid-evoked apoptosis should allow further refinement of this gene set. Based on these findings, in the next grant period our research will center on four specific aims. We will: 1) define by gene array analysis those genes whose altered expression is required for glucocorticoid-evoked CEM cell death; 2) test the hypothetical causal relationships between such genes; 3) obtain protein expression profiles unique to glucocorticoid-sensitive cells; and 4) test the role of the major, N-terminal transcription-activating domain of the GR in the above regulatory events. To carry out these experiments, we will combine expertise in molecular and cell biology, genomics, proteomics and bioinformatics. The resulting data will test the hypothesis that a network of interactive gene products is responsible for the glucocorticoid-evoked apoptosis. If our hypothesis is correct, this work will lead to the discovery of that network in a leukemic cell system, providing the foundation for detailed comparisons with other lymphoid systems, normal and malignant. This would open the way for studies of novel interventions against malignancies.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Endocrinology Study Section (END)
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Mufson, R Allan
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University of Texas Medical Br Galveston
Schools of Medicine
United States
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Webb, M S; Miller, A L; Howard, T L et al. (2018) Sequential gene regulatory events leading to glucocorticoid-evoked apoptosis of CEM human leukemic cells:interactions of MAPK, MYC and glucocorticoid pathways. Mol Cell Endocrinol 471:118-130
Aiyar, Sarah E; Park, Hoyong; Aldo, Paulomi B et al. (2010) TMS, a chemically modified herbal derivative of resveratrol, induces cell death by targeting Bax. Breast Cancer Res Treat 124:265-77
Garza, Anna S; Miller, Aaron L; Johnson, Betty H et al. (2009) Converting cell lines representing hematological malignancies from glucocorticoid-resistant to glucocorticoid-sensitive: signaling pathway interactions. Leuk Res 33:717-27
Ji, Zhenyu; Mei, Fang C; Miller, Aaron L et al. (2008) Protein kinase A (PKA) isoform RIIbeta mediates the synergistic killing effect of cAMP and glucocorticoid in acute lymphoblastic leukemia cells. J Biol Chem 283:21920-5
Webb, M S; Miller, A L; Thompson, E Brad (2007) In CEM cells the autosomal deafness gene dfna5 is regulated by glucocorticoids and forskolin. J Steroid Biochem Mol Biol 107:15-21
Miller, Aaron L; Webb, M Scott; Thompson, E Brad (2007) Comparison of two structurally diverse glucocorticoid receptor agonists: cortivazol selectively regulates a distinct set of genes separate from dexamethasone in CEM cells. Steroids 72:673-81
Ji, Zhenyu; Mei, Fang C; Johnson, Betty H et al. (2007) Protein kinase A, not Epac, suppresses hedgehog activity and regulates glucocorticoid sensitivity in acute lymphoblastic leukemia cells. J Biol Chem 282:37370-7
Ilies, Marc Antoniu; Seitz, William A; Johnson, Betty H et al. (2006) Lipophilic pyrylium salts in the synthesis of efficient pyridinium-based cationic lipids, gemini surfactants, and lipophilic oligomers for gene delivery. J Med Chem 49:3872-87
Copik, Alicja J; Webb, M Scott; Miller, Aaron L et al. (2006) Activation function 1 of glucocorticoid receptor binds TATA-binding protein in vitro and in vivo. Mol Endocrinol 20:1218-30
Miller, Aaron L; Webb, M Scott; Copik, Alicja J et al. (2005) p38 Mitogen-activated protein kinase (MAPK) is a key mediator in glucocorticoid-induced apoptosis of lymphoid cells: correlation between p38 MAPK activation and site-specific phosphorylation of the human glucocorticoid receptor at serine 211. Mol Endocrinol 19:1569-83

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