Thioredoxin-interacting protein (txnip) is a glucocorticoid-regulated primary response gene involved in mediating glucocorticoid-induced apoptosis.
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.
Wang
Z
Z
Department of Medicine and Pharmacology, Comprehensive Cancer Center, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland, OH 44106-7285, USA.
Rong
Y P
YP
Malone
M H
MH
Davis
M C
MC
Zhong
F
F
Distelhorst
C W
CW
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D017209:Apoptosis; D015152:Blotting, Northern; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D004252:DNA Mutational Analysis; D003907:Dexamethasone / Q000494:pharmacology*; D020869:Gene Expression Profiling; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D016399:Lymphoma, T-Cell / Q000235:genetics / Q000473:pathology*; D012333:RNA, Messenger; D013879:Thioredoxins / Q000235:genetics; D014407:Tumor Cells, Cultured
D000893:Anti-Inflammatory Agents; D002352:Carrier Proteins; D005938:Glucocorticoids; D012333:RNA, Messenger; C486715:TXNIP protein, human; D013879:Thioredoxins; D003907:Dexamethasone