Ras Suppresses TXNIP Expression by Restricting Ribosome Translocation

Ayer, Donald E.; Ye, Zhizhou

doi:10.1101/299354

Cited by 5 publications

(10 citation statements)

References 56 publications

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“…TXNIP is a potent negative regulator of glucose uptake; in fact, its loss or downregulation is sufficient to increase glucose uptake [19,39], suggesting that low TXNIP levels may be a common route to aerobic glycolysis common in cancer. Consistent with this hypothesis, TXNIP levels are generally lower in tumors compared to normal adjacent tissues [8], and a number of pro-growth/oncogenic pathways suppress TXNIP expression by a variety of mechanisms [19,20,34,[40][41][42]. Together these data suggest that the high demand for ATP driven by translation may result in a reduction of G6P, reduced MondoA transcriptional activity, and low TXNIP expression.…”

Section: Discussionmentioning

confidence: 60%

“…CHX induced TXNIP in MEFs and in MEFs that expressed an activated allele of HRAS (Fig. 4a) [34]. Further, TXNIP was induced by CHX-treatment in MEFs that lack the TSC2 tumor suppressor and in MDA-MDA-231 cells, which is a triple negative breast cancer (TNBC) cell line that harbors an inactivating mutation in TP53 and activating mutations in KRAS and BRAF (Fig.…”

Section: Mondoa and Txnip Are Required For The Cytotoxic Effects Of Rocamentioning

confidence: 88%

“…We showed that both MondoA and TXNIP are partially required for the growth suppressive activity of RocA, suggesting that the increase in MondoA activity and in TXNIP expression are just not correlated with protein synthesis inhibition, but may be critical for the full therapeutic response to protein synthesis blockade. Our previous work demonstrated that a number of progrowth pathways inhibit MondoA transcriptional activity and TXNIP expression [19,34,40,41], suggesting a potential limitation of protein synthesis inhibitors as cancer therapeutics. However, we show that RocA induced MondoA activity and TXNIP expression in several cell lines independent of oncogenic burden.…”

Section: Discussionmentioning

confidence: 99%

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Protein synthesis inhibitors stimulate MondoA transcriptional activity by driving an accumulation of glucose 6-phosphate

et al. 2020

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Background Protein synthesis is regulated by the availability of amino acids, the engagement of growth factor signaling pathways, and adenosine triphosphate (ATP) levels sufficient to support translation. Crosstalk between these inputs is extensive, yet other regulatory mechanisms remain to be characterized. For example, the translation initiation inhibitor rocaglamide A (RocA) induces thioredoxin-interacting protein (TXNIP). TXNIP is a negative regulator of glucose uptake; thus, its induction by RocA links translation to the availability of glucose. MondoA is the principal regulator of glucose-induced transcription, and its activity is triggered by the glycolytic intermediate, glucose 6-phosphate (G6P). MondoA responds to G6P generated by cytoplasmic glucose and mitochondrial ATP (mtATP), suggesting a critical role in the cellular response to these energy sources. TXNIP expression is entirely dependent on MondoA; therefore, we investigated how protein synthesis inhibitors impact its transcriptional activity. Methods We investigated how translation regulates MondoA activity using cell line models and loss-of-function approaches. We examined how protein synthesis inhibitors effect gene expression and metabolism using RNA-sequencing and metabolomics, respectively. The biological impact of RocA was evaluated using cell lines and patient-derived xenograft organoid (PDxO) models. Results We discovered that multiple protein synthesis inhibitors, including RocA, increase TXNIP expression in a manner that depends on MondoA, a functional electron transport chain and mtATP synthesis. Furthermore, RocA and cycloheximide increase mtATP and G6P levels, respectively, and TXNIP induction depends on interactions between the voltage-dependent anion channel (VDAC) and hexokinase (HK), which generates G6P. RocA treatment impacts the regulation of ~ 1200 genes, and ~ 250 of those genes are MondoA-dependent. RocA treatment is cytotoxic to triple negative breast cancer (TNBC) cell lines and shows preferential cytotoxicity against estrogen receptor negative (ER−) PDxO breast cancer models. Finally, RocA-driven cytotoxicity is partially dependent on MondoA or TXNIP. Conclusions Our data suggest that protein synthesis inhibitors rewire metabolism, resulting in an increase in mtATP and G6P, the latter driving MondoA-dependent transcriptional activity. Further, MondoA is a critical component of the cellular transcriptional response to RocA. Our functional assays suggest that RocA or similar translation inhibitors may show efficacy against ER− breast tumors and that the levels of MondoA and TXNIP should be considered when exploring these potential treatment options.

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Section: Discussionmentioning

confidence: 60%

Section: Mondoa and Txnip Are Required For The Cytotoxic Effects Of Rocamentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

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Protein synthesis inhibitors stimulate MondoA transcriptional activity by driving an accumulation of glucose 6-phosphate

et al. 2020

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“…TXNIP is a potent negative regulator of glucose uptake, in fact its loss or downregulation is sufficient to increase glucose uptake (19,40), suggesting that low TXNIP levels may be a common route to aerobic glycolysis common in cancer. Consistent with this hypothesis, TXNIP levels are generally lower in tumors compared to normal adjacent tissues (8), and a number of pro-growth/oncogenic pathways suppress TXNIP expression by a variety of mechanisms (19,20,35,(41)(42)(43). Together these data suggest that the high demand for ATP driven by translation, may result in a reduction of G6P,…”

Section: Protein Synthesis Inhibition Drives G6p Productionmentioning

confidence: 62%

“…PHB1 and PHB2)and their sequestration in the cytosol, which prevents Raf localization to the plasma membrane and its activation by Ras(45). Given our previous findings that that Ras-Raf signaling prevents MondoA transcriptional activity and TXNIP expression(35,41,42), it is possible that RocA-driven inhibition of Ras-Raf-MEK signaling also contributes to the increase in MondoA transcriptional activity we observe with RocA treatment.Finally, MondoA is required for the adaptive transcriptional program driven by RocA and accounts for ~20% of the RocA-induced changes in gene expression. Consistent with our recent demonstration that TXNIP and its paralog ARRDC4 are the principal direct MondoA targets in response to acidosis (12, 13, 16), their expression is also highly MondoA-and RocA-dependent in these experiments.…”

mentioning

confidence: 57%

Protein synthesis inhibitors stimulate MondoA transcriptional activity by driving an accumulation of glucose 6-phosphate

Wilde

Kaadige

Guillen

et al. 2020

Preprint

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Abstract BACKGROUND Protein synthesis is regulated by the availability of amino acids, the engagement of growth factor signaling pathways and ATP levels sufficient to support translation. Crosstalk between these inputs is extensive, yet other regulatory mechanisms remain to be characterized. For example, the translation initiation inhibitor Rocaglamide A (RocA) induces Thioredoxin Interacting Protein (TXNIP). TXNIP is a negative regulator of glucose uptake, thus its induction by RocA links translation to the availability of glucose. MondoA is the principal regulator of glucose-induced transcription and its activity is triggered by the glycolytic intermediate, glucose 6-phosphate (G6P). MondoA responds to G6P generated by cytoplasmic glucose and mitochondrial ATP (mtATP), suggesting a critical role in the cellular response to these energy sources. TXNIP expression is entirely dependent on MondoA, therefore, we investigated how protein synthesis inhibitors impact its transcriptional activity. METHODS We investigated how translation regulates MondoA activity using cell line models and loss-of-function approaches. We examined how protein synthesis inhibitors effect gene expression and metabolism using RNA-sequencing and metabolomics, respectively. The biological impact of RocA was evaluated using cell lines and Patient-Derived xenograft Organoid (PDxO) models. RESULTS We discovered that multiple protein synthesis inhibitors, including RocA, increase TXNIP expression in a manner that depends on MondoA, a functional electron transport chain and mtATP synthesis. Furthermore, RocA increases mtATP and G6P levels and TXNIP induction depends on interactions between the Voltage-Dependent Anion Channel (VDAC) and hexokinase, which generates G6P. RocA treatment impacts the regulation of ~1200 genes and ~250 of those genes are MondoA-dependent. RocA treatment is cytotoxic to Triple Negative Breast Cancer cell lines and shows preferential cytotoxicity against ER- PDxO breast cancer models. Finally, RocA-driven cytotoxicity is partially-dependent on MondoA or TXNIP. CONCLUSIONS Our data suggest that protein synthesis inhibitors rewire metabolism, resulting in an increase in mtATP and G6P, the latter driving MondoA-dependent transcriptional activity. Further, MondoA is a critical component of the cellular transcriptional response to RocA. Our functional assays suggest that RocA or similar translation inhibitors may show efficacy against ER- breast tumors and that the levels of MondoA and TXNIP should be considered when exploring these potential treatment options.

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Thioredoxin-Interacting Protein in Cancer and Diabetes

Masutani

2022

Antioxidants & Redox Signaling

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Significance: Thioredoxin interacting protein (Txnip) is an α-arrestin protein that acts as a cancer suppressor. Txnip is simultaneously a critical regulator of energy metabolism. Other alpha-arrestin proteins also play key roles in cell biology and cancer.Recent Advances: Txnip expression is regulated by multi-layered mechanisms including transcriptional regulation, microRNA, mRNA stabilization and protein degradation. The Txnip-based connection between cancer and metabolism has been widely recognized.Meanwhile, new aspects are proposed for the mechanism of action of Txnip including the regulation of RNA expression and autophagy. Arrestin domain containing 3 (ARRDC3), another α-arrestin protein, regulates endocytosis and signaling, whereas ARRDC1 and ARRDC4 regulate extracellular vesicle formation. Critical Issues:The mechanism of action of Txnip is still to be elucidated. The regulation of intracellular protein trafficking by arrestin family proteins has opened an emerging field of biology and medical research, which needs to be examined further.

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Ras Suppresses TXNIP Expression by Restricting Ribosome Translocation

Cited by 5 publications

References 56 publications

Protein synthesis inhibitors stimulate MondoA transcriptional activity by driving an accumulation of glucose 6-phosphate

Protein synthesis inhibitors stimulate MondoA transcriptional activity by driving an accumulation of glucose 6-phosphate

Protein synthesis inhibitors stimulate MondoA transcriptional activity by driving an accumulation of glucose 6-phosphate

Thioredoxin-Interacting Protein in Cancer and Diabetes

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