title: The glucocorticoid receptor is increased in Atm-/- thymocytes and in Atm-/- thymic lymphoma cells, and its nuclear translocation counteracts c-myc expression.
abstract: We have previously demonstrated that spontaneous DNA synthesis in immature thymocytes of Atm-/- mice is elevated, and that treatment with the glucocorticoid dexamethasone (Dex) attenuates this increased DNA synthesis and prevents the development of thymic lymphomas. Deregulation of c-myc may drive the uncontrolled proliferation of Atm-/- thymocytes, since upregulation of c-myc parallels the elevated DNA synthesis in the cells. In this study, we show that the glucocorticoid receptor (GR) is expressed at high levels in Atm-/- thymocytes and in Atm-/- thymic lymphoma cells, although serum glucocorticoid (GC) levels in Atm-/- mice are similar to those in Atm+/+ mice. In cultured Atm-/- thymic lymphoma cells treated with Dex, GR nuclear translocation occurs, resulting in suppression of DNA synthesis and c-myc expression at both the mRNA and protein levels. Interestingly, the GR antagonist RU486 also causes GR nuclear translocation, but does not affect DNA synthesis and c-myc expression in Atm-/- thymic lymphoma cells. As expected, RU486 reverses the suppressive effects of Dex on DNA synthesis and c-myc expression. Administration of Dex to Atm-/- mice decreases the elevated c-Myc protein levels in their thymocytes. These findings suggest that GC/GR signaling plays an important role in regulating c-myc expression in Atm-/- thymocytes and thymic lymphoma cells.
authors.affiliation: The University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, 1808 Park Road 1C, Smithville, TX 78957, USA. mingyan@mdanderson.org
authors.forename: Mingshan
authors.initials: M
authors.lastname: Yan
authors.forename: Xianghong
authors.initials: X
authors.lastname: Kuang
authors.forename: Virginia L
authors.initials: VL
authors.lastname: Scofield
authors.forename: Jianjun
authors.initials: J
authors.lastname: Shen
authors.forename: William S
authors.initials: WS
authors.lastname: Lynn
authors.forename: Paul K Y
authors.initials: PK
authors.lastname: Wong
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000235:genetics; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects / Q000235:genetics; D006727:Hormone Antagonists / Q000494:pharmacology; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D015735:Mifepristone / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis* / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013950:Thymus Gland / Q000378:metabolism* / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000378:metabolism
chemical_list: D018931:Antineoplastic Agents, Hormonal; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D006727:Hormone Antagonists; D016271:Proto-Oncogene Proteins c-myc; D011965:Receptors, Glucocorticoid; D025521:Tumor Suppressor Proteins; D015735:Mifepristone; D003907:Dexamethasone; D004247:DNA; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases