Thioredoxin-interacting protein ) is a glucocorticoid-regulated primary response gene involved in mediating glucocorticoid-induced apoptosis

• Published in: Oncogene Vol. 25; no. 13; pp. 1903 - 1913
• Main Authors: WANG, Z, RONG, Y. P, MALONE, M. H, DAVIS, M. C, ZHONG, F, DISTELHORST, C. W
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 23.03.2006; Nature Publishing Group
• Subjects: Ageing, cell death; Anti-Inflammatory Agents - pharmacology; Apoptosis; Biological and medical sciences; Blotting, Northern; Carrier Proteins - genetics; Carrier Proteins - physiology; Cell cycle; Cell death; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Dexamethasone; Dexamethasone - pharmacology; DNA Mutational Analysis; Fundamental and applied biological sciences. Psychology; Fusion protein; Gene deletion; Gene expression; Gene Expression Profiling; Glucocorticoids; Glucocorticoids - pharmacology; Hematologic and hematopoietic diseases; Humans; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphocytes T; Lymphoid cells; Lymphoma; Lymphoma, T-Cell - genetics; Lymphoma, T-Cell - pathology; Medical sciences; Molecular and cellular biology; Protein biosynthesis; Protein synthesis; Proteins; RNA, Messenger; RNA-mediated interference; Steroids; T-cell lymphoma; Thioredoxin; Thioredoxins - genetics; Thymocytes; Transcription; Tumor Cells, Cultured; Dexamethasone; Antiinflammatory agent; Malignant hemopathy; thioredoxin-interacting protein; txnip; Thioredoxin; Carcinogenesis; Glucocorticoid; Lymphoma; Protein; Gene; Lymphoproliferative syndrome; dexamethasone-induced gene; Apoptosis
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1209218

Glucocorticoid hormones induce apoptosis in lymphoid cells. This process is transcriptionally regulated and requires de novo RNA/protein synthesis. However, the full spectrum of glucocorticoid-regulated genes mediating this cell death process is unknown. Through gene expression profiling we discovered that the expression of thioredoxin-intereacting protein (txnip) mRNA is significantly induced by the glucocorticoid hormone dexamethasone not only in the murine T-cell lymphoma line WEHI7.2, but also in normal mouse thymocytes. This result was confirmed by Northern blot analysis in multiple models of dexamethasone-induced apoptosis. The induction of txnip mRNA by dexamethasone appears to be mediated through the glucocorticoid receptor as it is blocked in the presence of RU486, a glucocorticoid receptor antagonist. Deletion and mutation analysis of the txnip promoter identified a functional glucocorticoid response element in the txnip promoter. Reporter assays demonstrated that this glucocorticoid response element was necessary and sufficient for induction of txnip by dexamethasone. Expression of a GFP-TXNIP fusion protein was sufficient to induce apoptosis in WEHI7.2 cells, and repression of endogenous txnip by RNA interference inhibited dexamethasone-induced apoptosis in WEHI7.2 cells. Together, these findings indicate that txnip is a novel glucocorticoid-induced primary target gene involved in mediating glucocorticoid-induced apoptosis.