TXNIP potentiates Redd1-induced mTOR suppression through stabilization of Redd1

Ho, Jin‐Nyoung; Sk, Seo; Ys, Kim; Sh, Woo; Kh, Lee; Jy, Yi; Sj, Lee; Tb, Choe; Jh, Lee; An, Shi; Si, Hong; Park, IC

doi:10.1038/onc.2011.102

Cited by 79 publications

(60 citation statements)

References 39 publications

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“…7A), suggesting that the MondoA-TXNIP axis is required for the full metabolic stress response triggered by mTORC1 suppression. TXNIP has previously been shown to reduce mTORC1 activity via stabilization of Redd1, which drives TSC1/2 complex formation (34). However, our studies in TSC2-KO MEFs suggest that TXNIP can reduce mTORC1 activity independent of Redd1 and TSC2 (Fig.…”

Section: Discussioncontrasting

confidence: 54%

MondoA-Mlx Transcriptional Activity Is Limited by mTOR-MondoA Interaction

Kaadige

Yang

Wilde

et al. 2015

Molecular and Cellular Biology

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Mammalian target of rapamycin (mTOR) integrates multiple signals, including nutrient status, growth factor availability, and stress, to regulate cellular and organismal growth. How mTOR regulates transcriptional programs in response to these diverse stimuli is poorly understood. MondoA and its obligate transcription partner Mlx are basic helix-loop-helix leucine zipper (bHLHZip) transcription factors that sense and execute a glucose-responsive transcriptional program. MondoA-Mlx complexes activate expression of thioredoxin-interacting protein (TXNIP), which is a potent inhibitor of cellular glucose uptake and aerobic glycolysis. Both mTOR and MondoA are central regulators of glucose metabolism, yet whether they interact physically or functionally is unknown. We show that inhibition of mTOR induces MondoA-dependent expression of TXNIP, coinciding with reduced glucose uptake. Mechanistically, mTOR binds to MondoA in the cytoplasm and prevents MondoA-Mlx complex formation, restricting MondoA's nuclear entry and reducing TXNIP expression. Further, we show that mTOR inhibitors and reactive oxygen species (ROS) regulate interaction between MondoA and mTOR in an opposing manner. Like mTOR's suppression of the MondoA-TXNIP axis, MondoA can also suppress mTOR complex 1 (mTORC1) activity via its direct transcriptional regulation of TXNIP. Collectively, these studies reveal a regulatory relationship between mTOR and the MondoA-TXNIP axis that we propose contributes to glucose homeostasis. Mammalian target of rapamycin (mTOR) plays a central role in cell growth and proliferation, and its dysregulation contributes to many diseases, including cancer and diabetes. mTOR is a Ser/Thr kinase that exists in two functionally distinct multiprotein complexes, rapamycin-sensitive mTOR complex 1 (mTORC1) and rapamycin-insensitive mTOR complex 2 (mTORC2). mTORC1 promotes protein synthesis by directly phosphorylating ribosomal S6 kinase (S6K) and eukaryotic translation initiation factor 4E (4E-BP1), whereas mTORC2 promotes cell survival and metabolism by phosphorylating Akt (1). Inhibition of mTOR affects global transcription, with genes driving anabolic or catabolic processes being generally repressed or activated, respectively (2-6). Because mTOR integrates progrowth and growth-suppressive signals, it is likely that mTOR regulates diverse transcription factors and chromatin modifiers to induce or repress gene expression; however, our knowledge of the transcription factors regulated by mTOR is limited (7,8).We focus on a family of transcription factors that respond to environmental and intracellular cues. MondoA and its dimerization partner Mlx are members of the basic helix-loop-helix leucine zipper (bHLHZip) family of transcription factors (9). MondoAMlx complexes shuttle between the cytosol and the nucleus; however, in response to high levels of glucose, they accumulate in the nucleus, bind the promoters of target genes, and regulate their expression. MondoA-Mlx complexes are important, perhaps the principal, regulators of glucose-in...

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Section: Discussioncontrasting

confidence: 54%

MondoA-Mlx Transcriptional Activity Is Limited by mTOR-MondoA Interaction

Kaadige

Yang

Wilde

et al. 2015

Molecular and Cellular Biology

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“…As a result of the broad cellular roles of thioredoxin, Txnip is implicated in diverse cellular processes including proliferation, apoptosis, and differentiation (34). A recent study identified TXNIP as an upstream regulator of mTOR activity (35), but here we report mTOR as a regulator of TXNIP. TXNIP was significantly up-regulated by PP242 but not by rapamycin or DG2 (Fig.…”

Section: Pp242 But Not Rapamycin Causes Global Transcriptional Rewiringmentioning

confidence: 70%

The mammalian target of rapamycin regulates cholesterol biosynthetic gene expression and exhibits a rapamycin-resistant transcriptional profile

Wang

Ducker

Barczak

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

100

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The mammalian target of rapamycin (mTOR) is a central regulator of cell growth and proliferation in response to growth factor and nutrient signaling. Consequently, this kinase is implicated in metabolic diseases including cancer and diabetes, so there is great interest in understanding the complete spectrum of mTOR-regulated networks. mTOR exists in two functionally distinct complexes, mTORC1 and mTORC2, and whereas the natural product rapamycin inhibits only a subset of mTORC1 functions, recently developed ATP-competitive mTOR inhibitors have revealed new roles for both complexes. A number of studies have highlighted mTORC1 as a regulator of lipid homeostasis. We show that the ATP-competitive inhibitor PP242, but not rapamycin, significantly down-regulates cholesterol biosynthesis genes in a 4E-BP1-dependent manner in NIH 3T3 cells, whereas S6 kinase 1 is the dominant regulator in hepatocellular carcinoma cells. To identify other rapamycin-resistant transcriptional outputs of mTOR, we compared the expression profiles of NIH 3T3 cells treated with rapamycin versus PP242. PP242 caused 1,666 genes to be differentially expressed whereas rapamycin affected only 88 genes. Our analysis provides a genomewide view of the transcriptional outputs of mTOR signaling that are insensitive to rapamycin.sterol regulatory element-binding protein-2 | eIF4E-binding protein-1 phosphorylation | 3-hydroxy-3-methylglutaryl-CoA reductase | thioredoxin interacting protein | expression array

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“…Regulated in development and DNA damage responses 1 (Redd1) protein is a negative regulator of mTOR activity. Txnip interacts with Redd1 and protects it from proteasomal degradation, leading to decreased mTOR activity (130).…”

mentioning

confidence: 99%

Thioredoxin and Thioredoxin Target Proteins: From Molecular Mechanisms to Functional Significance

Lee

Kim

Lee

2013

Antioxidants & Redox Signaling

349

263

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The thioredoxin (Trx) system is one of the central antioxidant systems in mammalian cells, maintaining a reducing environment by catalyzing electron flux from nicotinamide adenine dinucleotide phosphate through Trx reductase to Trx, which reduces its target proteins using highly conserved thiol groups. While the importance of protecting cells from the detrimental effects of reactive oxygen species is clear, decades of research in this field revealed that there is a network of redox-sensitive proteins forming redox-dependent signaling pathways that are crucial for fundamental cellular processes, including metabolism, proliferation, differentiation, migration, and apoptosis. Trx participates in signaling pathways interacting with different proteins to control their dynamic regulation of structure and function. In this review, we focus on Trx target proteins that are involved in redox-dependent signaling pathways. Specifically, Trx-dependent reductive enzymes that participate in classical redox reactions and redox-sensitive signaling molecules are discussed in greater detail. The latter are extensively discussed, as ongoing research unveils more and more details about the complex signaling networks of Trx-sensitive signaling molecules such as apoptosis signal-regulating kinase 1, Trx interacting protein, and phosphatase and tensin homolog, thus highlighting the potential direct and indirect impact of their redox-dependent interaction with Trx. Overall, the findings that are described here illustrate the importance and complexity of Trx-dependent, redox-sensitive signaling in the cell. Our increasing understanding of the components and mechanisms of these signaling pathways could lead to the identification of new potential targets for the treatment of diseases, including cancer and diabetes.

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TXNIP potentiates Redd1-induced mTOR suppression through stabilization of Redd1

Cited by 79 publications

References 39 publications

MondoA-Mlx Transcriptional Activity Is Limited by mTOR-MondoA Interaction

MondoA-Mlx Transcriptional Activity Is Limited by mTOR-MondoA Interaction

The mammalian target of rapamycin regulates cholesterol biosynthetic gene expression and exhibits a rapamycin-resistant transcriptional profile

Thioredoxin and Thioredoxin Target Proteins: From Molecular Mechanisms to Functional Significance

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