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Title: The regulation of TXNIP Gene Expression
Authors: YU FAXING
Keywords: Txnip, glucose, adenosine, nitrients, oxidative phosphorylation, transcription
Issue Date: 14-Jun-2009
Citation: YU FAXING (2009-06-14). The regulation of TXNIP Gene Expression. ScholarBank@NUS Repository.
Abstract: Thioredoxin interacting protein (Txnip) is a multifunctional protein involved in regulation of cell cycle events and cellular metabolism. The expression of Txnip is induced by glucose, and this induction is mediated by a carbohydrate response element (ChoRE) on Txnip promoter and its associated transcription factors, MondoA and Max-like protein X (MLX). In this study, I have discovered 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. The induction of Txnip expression by adenosine-containing molecules is glucose dependent, and MondoA and MLX have been shown 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, and this suggests that these molecules may modulate the kinetics of glucose homeostasis.I have also studied the underlying regulatory mechanisms of glucose and adenosine-containing molecules on Txnip expression. 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. I 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 presumably through inducing dynamic chromatin changes in response to diverse physiological inducers.
Appears in Collections:Ph.D Theses (Open)

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