Theses & Dissertations

Glucose-dependent transcriptional activity of the mondoa:MLX heterodimer

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Publication Type dissertation
School or College School of Medicine
Department Oncological Sciences
Author Peterson, Christopher William
Title Glucose-dependent transcriptional activity of the mondoa:MLX heterodimer
Date 2010-03-26
Description The transcriptional regulation of glucose homeostasis is a central tenet of biology. In metazoans, this function is performed by the Myc-related transcriptional activators, MondoA and ChREBP. ChREBP operates predominantly in liver and promotes the conversion of high levels of intracellular glucose to lipid for energy storage and membrane synthesis. MondoA operates predominantly in skeletal muscle and promotes the conversion of high levels of intracellular glucose to ATP for immediate use in this highly catabolic tissue type. The experiments presented here detail how MondoA:Mlx heterodimers sense and respond to glucose. The hexokinase-dependent phosphorylation of glucose to G6P stimulates nuclear accumulation and transcriptional activity of MondoA:Mlx, which in turn governs 75% of glucose-dependent transcription. In high glucose conditions, MondoA activates a negative regulator of glucose uptake, thioredoxin interacting protein (TXNIP) to downregulate further glucose uptake. This negative feedback loop is conserved in all cell types tested. MondoA:Mlx shuttles between mitochondria and the nucleus in high and low glucose conditions; G6P and heterodimerization with Mlx promote nuclear accumulation of the heterodimer. The Nterminal Mondo Conserved Regions (MCRs) of MondoA define the glucose-dependent character of the protein. In conjunction with the C-terminal DNA binding domain, the MCRs mediate activation of MondoA:Mlx heterodimers through three distinct steps: nuclear accumulation, promoter occupancy, and coactivator recruitment. Each of these The transcriptional regulation of glucose homeostasis is a central tenet of biology. In metazoans, this function is performed by the Myc-related transcriptional activators, MondoA and ChREBP. ChREBP operates predominantly in liver and promotes the conversion of high levels of intracellular glucose to lipid for energy storage and membrane synthesis. MondoA operates predominantly in skeletal muscle and promotes the conversion of high levels of intracellular glucose to ATP for immediate use in this highly catabolic tissue type. The experiments presented here detail how MondoA:Mlx heterodimers sense and respond to glucose. The hexokinase-dependent phosphorylation of glucose to G6P stimulates nuclear accumulation and transcriptional activity of MondoA:Mlx, which in turn governs 75% of glucose-dependent transcription. In high glucose conditions, MondoA activates a negative regulator of glucose uptake, thioredoxin interacting protein (TXNIP) to downregulate further glucose uptake. This negative feedback loop is conserved in all cell types tested. MondoA:Mlx shuttles between mitochondria and the nucleus in high and low glucose conditions; G6P and heterodimerization with Mlx promote nuclear accumulation of the heterodimer. The Nterminal Mondo Conserved Regions (MCRs) of MondoA define the glucose-dependent character of the protein. In conjunction with the C-terminal DNA binding domain, the MCRs mediate activation of MondoA:Mlx heterodimers through three distinct steps: nuclear accumulation, promoter occupancy, and coactivator recruitment. Each of theseThe transcriptional regulation of glucose homeostasis is a central tenet of biology. In metazoans, this function is performed by the Myc-related transcriptional activators, MondoA and ChREBP. ChREBP operates predominantly in liver and promotes the conversion of high levels of intracellular glucose to lipid for energy storage and membrane synthesis. MondoA operates predominantly in skeletal muscle and promotes the conversion of high levels of intracellular glucose to ATP for immediate use in this highly catabolic tissue type. The experiments presented here detail how MondoA:Mlx heterodimers sense and respond to glucose. The hexokinase-dependent phosphorylation of glucose to G6P stimulates nuclear accumulation and transcriptional activity of MondoA:Mlx, which in turn governs 75% of glucose-dependent transcription. In high glucose conditions, MondoA activates a negative regulator of glucose uptake, thioredoxin interacting protein (TXNIP) to downregulate further glucose uptake. This negative feedback loop is conserved in all cell types tested. MondoA:Mlx shuttles between mitochondria and the nucleus in high and low glucose conditions; G6P and heterodimerization with Mlx promote nuclear accumulation of the heterodimer. The Nterminal Mondo Conserved Regions (MCRs) of MondoA define the glucose-dependent character of the protein. In conjunction with the C-terminal DNA binding domain, the MCRs mediate activation of MondoA:Mlx heterodimers through three distinct steps: nuclear accumulation, promoter occupancy, and coactivator recruitment. Each of these steps is glucose-dependent, and requires the 12-amino acid MCRII domain. In sum, MondoA is essential for intracellular glucose homeostasis, MondoA activity is regulated at multiple glucose-dependent steps, and MondoA-dependent target genes control intracellular glucose availability.
Type Text
Publisher University of Utah
Subject ARRDC4; ChREBP; Glucose metabolism; Mitochondria; MondoA; TXNIP
Subject LCSH Glucose -- Metabolism - Regulation
Subject MESH Cell Biology; Molecular Biology; MONDOA protein, human; Glycolysis; Transcription Factors
Dissertation Institution University of Utah
Dissertation Name PhD
Language eng
Relation is Version of Digital reproduction of "Glucose-dependent transcriptional activity of the mondoa:mlx heterodimer." Spencer S. Eccles Health Sciences Library." Print version of "Glucose-dependent transcriptional activity of the mondoa:mlx heterodimer." available at J. Willard Marriott Library Special Collection.
Rights Management © Christopher William Peterson
Format Medium application/pdf
Format Extent 5,538,102 bytes
Source Original: University of Utah Spencer S. Eccles Health Sciences Library; Also in Marriott Library Special Collectios, QP6.5 2010 .P48
Conversion Specifications Original scanned on Fujitsu fi-5220G as 400 dpi to pdf using ABBYY FineReader 10
ARK ark:/87278/s6fr0b6z
Setname ir_etd
ID 193520
Reference URL https://collections.lib.utah.edu/ark:/87278/s6fr0b6z