Journal
ONCOGENE
Volume 25, Issue 13, Pages 1903-1913Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1209218
Keywords
glucocorticoid; apoptosis; lymphoma; dexamethasone-induced gene; thioredoxin-interacting protein; txnip
Funding
- NCI NIH HHS [CP30 CA43703, T32 CA59366, R01 CA42755] Funding Source: Medline
- NHLBI NIH HHS [T32 HL07147] Funding Source: Medline
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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 pro. ling 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.
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