title: REDD1/DDIT4-independent mTORC1 inhibition and apoptosis by glucocorticoids in thymocytes.
abstract: Glucocorticoids induce apoptosis in lymphocytes and are commonly used to treat hematologic malignancies. However, they are also associated with significant adverse effects and their molecular mechanism of action is not fully understood. Glucocorticoid treatment induces expression of the mTORC1 inhibitor Regulated in Development and DNA Damage Response 1 (REDD1), also known as DNA-Damage Inducible Transcript 4 (DDIT4), and mTORC1 inhibition may distinguish glucocorticoid-sensitive from glucocorticoid-resistant acute lymphoblastic leukemia (ALL). Interestingly, REDD1 induction was impaired in glucocorticoid-resistant ALL cells and inhibition of mTORC1 using rapamycin restored glucocorticoid sensitivity. These data suggest that REDD1 may be essential for the response of ALL cells to glucocorticoids. To further investigate the role of REDD1, we evaluated the effects of glucocorticoids on primary thymocytes from wild-type and REDD1-deficient mice. Glucocorticoid-mediated apoptosis was blocked by a glucocorticoid receptor antagonist and by an inhibitor of transcription, which interfered with REDD1 induction and mTORC1 inhibition. However, REDD1 ablation had no effect on glucocorticoid-induced mTORC1 inhibition and apoptosis in thymocytes ex vivo. Overall, these data not only demonstrate the contextual differences of downstream signaling following glucocorticoid treatment but also provide a better mechanistic understanding of the role of REDD1.
  
  
  CONCLUSIONS
  These molecular findings underlying glucocorticoid action and the role of REDD1 are fundamental for the design of novel, more efficacious, and less toxic analogs. Mol Cancer Res; 12(6); 867-77. ©2014 AACR.
authors.affiliation: Authors' Affiliations: Division of Hematology-Oncology, Department of Internal Medicine, Department of Developmental Biology, and the Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Wolff
authors.affiliation: Department of Developmental Biology, and the.
authors.forename: Renée M
authors.initials: RM
authors.lastname: McKay
authors.affiliation: Authors' Affiliations: Division of Hematology-Oncology, Department of Internal Medicine, Department of Developmental Biology, and the Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas james.brugarolas@utsouthwestern.edu.
authors.forename: James
authors.initials: J
authors.lastname: Brugarolas
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002648:Child; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D060168:Thymocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: C469991:DDIT4 protein, human; C469992:Ddit4 protein, mouse; D005938:Glucocorticoids; D046912:Multiprotein Complexes; D014157:Transcription Factors; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases