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Rictor orchestrates β-catenin/FOXO balance by maintaining redox homeostasis during development of ovarian cancer

ABSTRACT: Rictor orchestrates β-catenin/FOXO balance by maintaining redox homeostasis during development of ovarian cancer

PROVIDER: PRJNA494346 | ENA |

REPOSITORIES: ENA

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Rictor orchestrates β-catenin/FOXO balance by maintaining redox homeostasis during development of ovarian cancer

Project description:Rictor/mTORC2 has been demonstrated to have important roles in cancer development and progression in a number of solid and hematologic malignancies. However, little is known about the role of Rictor/mTORC2 in ovarian cancer pathophysiology. Herein, using conditional Rictor knockout mice, we were able to demonstrate that Rictor deletion disrupted glutathione metabolism through Nrf2-dependent, AKT-independent signaling and induced intracellular oxidative stress during the malignant transformation of Kras/Pten-mutant ovarian surface epithelial cells. Elevated reactive oxygen species and activated FOXO3a in Rictor-deleted cells strikingly shifts the functional interaction of β-catenin from TCF to FOXO3a, which strongly inhibits classical Wnt/β-catenin signaling. Our findings emphasize a pivotal role of Rictor in orchestrating crosstalk between the PI3K/AKT and Wnt/β-catenin signaling in the development of ovarian cancer.

2025-03-21 | GSE120743 | GEO

NRF2 Is Required for Neonatal Beta-Cell Growth by Maintaining Redox Balance and Promoting Mitochondrial Biogenesis and Function

Project description:Due to the limited expression of several antioxidant enzymes, β-cells are highly vulnerable to high ROS levels, which can lead to the reduction of functional β-cell mass. During early postnatal ages, both human and rodent β-cells go through a burst of proliferation that quickly declines with age. Here we discovered that the expression of the master antioxidant regulator, Nrf2, is increased during this postnatal burst of β-cell proliferation in humans. Additionally, data from β-cell specific Nrf2 deletion in mice demonstrated that Nrf2 is required for β-cell proliferation, β-cell survival, β-cell identity and β-cell mass expansion at early stages of life. Daily administration of antioxidant NAC to newborn mice showed that Nrf2 mechanism of action strongly relies on maintaining normal redox balance. Interestingly, RNAseq of islets isolated from β-cell specific Nrf2 deleted mice suggests that Nrf2 regulates neonatal β-cell proliferation by promoting mitochondrial ATP synthesis. Our study highlights Nrf2 as an essential transcription factor for maintaining redox balance as well as mitochondrial biogenesis and function to support neonatal β-cell growth and for maintaining functional β-cell mass in adulthood under metabolic stress.

2023-12-19 | GSE242718 | GEO

Rictor Plays a Pivotal Role in Maintaining Quiescence as well as Stemness of Leukemia Stem Cells in MLL-Driven Leukemia

Project description:Little is known about the roles of Rictor/mTORC2 in the leukemogenesis of AML. Here, we demonstrated that Rictor is essential for the maintenance of MLL-driven leukemia by preventing LSCs from exhaustion. Rictor depletion led to a reactive activation of mTORC1 signaling by facilitating the assembly of mTORC1. Hyperactivated mTORC1 signaling in turn drove LSCs into cycling, compromised the quiescence of LSCs and eventually exhausted their capacity to generate leukemia. At the same time, loss of Rictor had led to a reactive activation of FoxO3a in leukemia cells, which acts as negative feedback to restrain greater over-reactivation of mTORC1 activity and paradoxically protects leukemia cells from exhaustion. Simultaneous depletion of Rictor and FoxO3a enabled rapid exhaustion of MLL LSCs and a quick eradication of MLL leukemia. As such, our present findings highlighted a pivotal regulatory axis of Rictor-FoxO3a in maintaining quiescence and the stemness of LSCs. To understand the critical molecular events caused by Rictor loss in MLL-AF9-driven leukemia,the K+Gâ mice BM cells were sorted from the 1st BMT of RictorÎ/Î(MA9_R1,MA9_R2,MA9_R3) or control(MA9_C1,MA9_C2,MA9_C3), and subjected to microarray analysis on Affymetrix microarrays.Furthermore, the MLL-NRIP3-driven mice model was chosen for further examination.The K+Gâ mice BM cells were sorted from the 1st BMT of RictorÎ/Î(MN3_R1,MN3_R2,MN3_R3) or control(MN3_C1,MN3_C2,MN3_C3), and subjected to microarray analysis on Affymetrix microarrays.

2016-07-19 | E-GEOD-84505 | biostudies-arrayexpress

Rictor Plays a Pivotal Role in Maintaining Quiescence as well as Stemness of Leukemia Stem Cells in MLL-Driven Leukemia

2016-07-19 | GSE84505 | GEO

NTRC controls chloroplast redox homeostasis through the regulation of the redox balance of 2-Cys Prxs in Arabidopsis

Project description:Thiol-dependent redox regulation is essential for the rapid adaptation of chloroplast metabolism to unpredictable changes of light intensity. The disulfide reductase activity of thioredoxins (Trxs), which relies on photo-reduced ferredoxin (Fdx) and a Fdx-dependent Trx reductase (FTR), constitutes the Fdx-FTR-Trxs system, which links chloroplast redox regulation to light. In addition, chloroplasts harbor an NADPH-dependent Trx reductase (NTR) with a joint Trx domain, NTRC. The activity of these two redox systems is integrated by the balance of the hydrogen peroxide scavenging enzyme 2-Cys peroxiredoxin (2-Cys Prx), which thus plays a key role in maintaining the reducing capacity of chloroplast Trxs in response to light intensity. Based on the severe phenotype of mutant lines lacking NTRC, it is clear that this enzyme plays an essential role in chloroplast redox homeostasis. However, whether the function of NTRC depends on its capacity of reduce 2-Cys Prxs or has additional targets remains unknown. Here, we have addressed this issue by a comparative analysis of the triple mutant of Arabidopsis thaliana, ntrc-2cpab, simultaneously lacking 2-Cys Prxs and NTRC, and the double mutant 2cpab lacking 2-Cys Prxs. The phenotype of the ntrc-2cpab mutant is indistinguishable of the 2cpab mutant, as shown by growth rate, photosynthesis performance, light-dependent redox regulation of enzyme activity and comparative transcriptomics based RNA-Seq. Based on these results, we propose that the function of NTRC in chloroplast redox homeostasis is exerted by the regulation of the redox balance of 2-Cys Prxs rather than by the direct reduction of additional targets.

2021-09-09 | GSE147793 | GEO

NRF2 Is Required for Neonatal Beta-Cell Growth by Maintaining Redox Balance and Promoting Mitochondrial Biogenesis and Function

Project description:NRF2 Is Required for Neonatal Beta-Cell Growth by Maintaining Redox Balance and Promoting Mitochondrial Biogenesis and Function

| PRJNA1014415 | ENA

Anakinra restores cellular proteostasis by coupling mitochondrial redox balance to autophagy

Project description:Anakinra restores cellular proteostasis by coupling mitochondrial redox balance to autophagy

| PRJNA780423 | ENA

Super-enhancer-driven MLX mediates redox balance maintanance via SLC7A11 in osteosarcoma

Project description:A systematic analysis of super-enhancers identified MLX as a potential oncogene in osteosarcoma. Knockdown of MLX impaired tumor aggressiveness in vitro and in vivo, suggesting oncogenic properties of MLX. Mechanistically, silencing of MLX downregulates SLC7A11, a key gene encoding glutamate/cystine antiporter, to attenuate the uptake of cystine and interrupt the redox balance, leading to ferroptotic cell death. Pharmacological inhibition of SLC7A11 triggered massive ferroptosis and caused impaired tumor growth, providing a promising approach for osteosarcoma treatment.

2023-08-08 | GSE220173 | GEO

NTRC controls chloroplast redox homeostasis through the regulation of the redox balance of 2-Cys Prxs in Arabidopsis

Project description:NTRC controls chloroplast redox homeostasis through the regulation of the redox balance of 2-Cys Prxs in Arabidopsis

| PRJNA616378 | ENA

Nrf1 promotes heart regeneration and repair by regulating proteostasis and redox balance

Project description:Nrf1 promotes heart regeneration and repair by regulating proteostasis and redox balance

| PRJNA686963 | ENA