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Adenosine-Containing Molecules Amplify Glucose Signaling and Enhance Txnip Expression

Institute of Molecular and Cell Biology (F.-X.Y., S.-R.G., R.-P.D., Y.L.), Singapore 138673; and Department of Biochemistry (Y.L.), National University of Singapore, Singapore 117597

Address all correspondence and requests for reprints to: Dr. Yan Luo, Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673. E-mail: yluo{at}imcb.a-star.edu.sg.

Eukaryotic cells sense extracellular glucose concentrations via diverse mechanisms to regulate the expression of genes involved in metabolic control. One such example is the tight correlation between the expression of thioredoxin-interacting protein (Txnip) and extracellular glucose levels. In this report, we show that the transcription of the Txnip gene is induced by adenosine-containing molecules, of which an intact adenosine moiety is necessary and sufficient. Txnip promoter contains a carbohydrate response element, which mediates the induction of Txnip expression by these molecules in a glucose-dependent manner. Max-like protein X and MondoA are transcription factors previously shown to stimulate glucose-dependent Txnip expression and are shown here to convey stimulatory signals from extracellular adenosine-containing molecules to the Txnip promoter. The regulatory role of these molecules may be exerted via amplifying glucose signaling. Hence, this revelation may pave the way for interventions aimed toward metabolic disorders resulting from abnormal glucose homeostasis.