Abstract B100: The expression of thioredoxin-interacting protein (Txnip): Modulators, mechanisms and functions

Abstract

Abstract Thioredoxin interacting protein (Txnip) is a multifunctional protein involved in regulation of cell cycle events and cellular metabolism; the expression of the Txnip gene is down-regulated in a large range of cancer cells and up-regulated in diabetic and pre-diabetic patients. Therefore, Txnip might be a link between metabolism and cancer development, and the study of regulatory mechanism(s) that governs Txnip expression has important clinical relevance. The expression of Txnip is induced by glucose, which is mediated by an earlier defined carbohydrate response element (ChoRE) on Txnip promoter and its associated transcription factors, MondoA (or its homolog, ChREBP) and Max-like protein X (MLX). Here, we show that the transcription of the Txnip gene is induced by an array of adenosine-containing molecules, of which an intact adenosine moiety is necessary and sufficient. When cells are treated with adenosine-containing molecules, the glucose uptake is inhibited and cell cycle progression is retarded, probably attributed to enhanced Txnip expression. The induction of Txnip expression by adenosine-containing molecules is in a glucose-dependent manner, and MondoA and MLX are known to convey stimulatory signals from extracellular molecules to the Txnip promoter. Therefore, the regulatory role of adenosine-containing molecules is exerted via amplifying glucose signaling, hence suggesting that these molecules may modulate the kinetics of glucose homeostasis. To gain more knowledge about the regulation of Txnip expression, we have also studied the underlying regulatory mechanisms of glucose and adenosine-containing molecules on Txnip expression in details. An additional ChoRE on the promoter of Txnip gene has been identified, and this ChoRE is able to recruit MondoA and MLX in a similar fashion as the previously identified ChoRE in vitro and in vivo. Both ChoREs function cooperatively to mediate optimal Txnip expression under glucose or adenosine-containing molecules treatment. However, these two ChoREs are not sufficient to mediate the induction of Txnip expression by glucose or adenosine-containing molecules, and two CCAAT boxes, both can recruit nuclear factor Y (NF-Y) to the Txnip promoter, are also required for the induction. We also found that the function of ChoREs and associated factors is contingent on tandem CCAAT boxes, in that the occupancy of the Txnip promoter by the CCAAT box-associated NF-Y is a prerequisite for efficacious recruitment of MondoA/MLX to ChoREs under glucose stimulation. Such a strategy suggests a synergy between NF-Y and MondoA/MLX in enhancing Txnip expression, which leads us to propose a model for the glucose-dependent Txnip expression mediated by dynamic chromatin changes in response to diverse physiological inducers. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B100.