REDD1 Is Essential for Optimal T Cell Proliferation and Survival

Reuschel, Emma L.; Wang, JiangFang; Shivers, Debra K.; Muthumani, Kar; Weiner, David B.; Ma, Zhengyu; Finkel, Terri H.

doi:10.1371/journal.pone.0136323

Cited by 27 publications

(27 citation statements)

References 39 publications

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“…These results indicate that REDD1mediated autophagy may be a novel target to sensitize BUC cells to Taxol chemotherapy. REDD1 expression can be induced by MAPK and PKA signaling pathways (42,43), and can also be negatively regulated by other factors such as Ezrin, T-cell acute leukemia 1 (TAL1), and IL6 (44)(45)(46). Here we make the novel discovery that REDD1 is negatively regulated by miR-22.…”

Section: Discussionmentioning

confidence: 98%

Inhibition of REDD1 Sensitizes Bladder Urothelial Carcinoma to Paclitaxel by Inhibiting Autophagy

Zeng

Liu

Cao

et al. 2018

Clinical Cancer Research

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Regulated in development and DNA damage response-1 (REDD1) is a stress-related protein and is involved in the progression of cancer. The role and regulatory mechanism of REDD1 in bladder urothelial carcinoma (BUC), however, is yet unidentified. The expression of REDD1 in BUC was detected by Western blot analysis and immunohistochemistry (IHC). The correlation between REDD1 expression and clinical features in patients with BUC were assessed. The effects of REDD1 on cellular proliferation, apoptosis, autophagy, and paclitaxel sensitivity were determined both and Then the targeted-regulating mechanism of REDD1 by miRNAs was explored. Here the significant increase of REDD1 expression is detected in BUC tissue, and REDD1 is first reported as an independent prognostic factor in patients with BUC. Silencing REDD1 expression in T24 and EJ cells decreased cell proliferation, increased apoptosis, and decreased autophagy, whereas the ectopic expression of REDD1 in RT4 and BIU87 cells had the opposite effect. In addition, the REDD1-mediated proliferation, apoptosis, and autophagy are found to be negatively regulated by miR-22 , which intensify the paclitaxel sensitivity via inhibition of the well-acknowledged REDD1-EEF2K-autophagy axis. AKT/mTOR signaling initially activated or inhibited in response to silencing or enhancing REDD1 expression and then recovered rapidly. Finally, the inhibited REDD1 expression by either RNAi or miR-22 sensitizes BUC tumor cells to paclitaxel in a subcutaneous transplant carcinoma model REDD1 is confirmed as an oncogene in BUC, and antagonizing REDD1 could be a potential therapeutic strategy to sensitize BUC cells to paclitaxel. .

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Section: Discussionmentioning

confidence: 98%

Inhibition of REDD1 Sensitizes Bladder Urothelial Carcinoma to Paclitaxel by Inhibiting Autophagy

Zeng

Liu

Cao

et al. 2018

Clinical Cancer Research

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“…Redd1-null mice are protected against both of these biochemical changes and the behavioral manifestations of stress-induced depression (Ota et al 2014). The contribution of REDD1 to human cancer has remained uncertain, as Redd1-null mice do not die prematurely or exhibit tumor predisposition, and studies have reported mixed results regarding the contribution of REDD1 to cell proliferation and survival relevant to tumorigenesis (DeYoung et al 2008;Reuschel et al 2015;Lipina and Hundal 2016).…”

mentioning

confidence: 99%

REDD1 loss reprograms lipid metabolism to drive progression of RAS mutant tumors

et al. 2020

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Human cancers with activating RAS mutations are typically highly aggressive and treatment-refractory, yet RAS mutation itself is insufficient for tumorigenesis, due in part to profound metabolic stress induced by RAS activation. Here we show that loss of REDD1, a stress-induced metabolic regulator, is sufficient to reprogram lipid metabolism and drive progression of RAS mutant cancers. Redd1 deletion in genetically engineered mouse models (GEMMs) of KRAS-dependent pancreatic and lung adenocarcinomas converts preneoplastic lesions into invasive and metastatic carcinomas. Metabolic profiling reveals that REDD1-deficient/RAS mutant cells exhibit enhanced uptake of lysophospholipids and lipid storage, coupled to augmented fatty acid oxidation that sustains both ATP levels and ROSdetoxifying NADPH. Mechanistically, REDD1 loss triggers HIF-dependent activation of a lipid storage pathway involving PPARγ and the prometastatic factor CD36. Correspondingly, decreased REDD1 expression and a signature of REDD1 loss predict poor outcomes selectively in RAS mutant but not RAS wild-type human lung and pancreas carcinomas. Collectively, our findings reveal the REDD1-mediated stress response as a novel tumor suppressor whose loss defines a RAS mutant tumor subset characterized by reprogramming of lipid metabolism, invasive and metastatic progression, and poor prognosis. This work thus provides new mechanistic and clinically relevant insights into the phenotypic heterogeneity and metabolic rewiring that underlies these common cancers.

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“…Elevated DDIT4 levels in CD4 + T cells may have interesting implications for maintenance of T cell differentiation and homeostasis. Reports demonstrate that DDIT4 is essential for control of autophagy [35] as well as optimal T cell proliferation and survival [36]. Importantly, RBPJ upregulation may play a key role in maintaining, if not decreasing, Th17/Treg ratios and still elevated FOXP1 levels may indicate enhanced regulation of quiescence in CD4 + T cells [27].…”

Section: Discussionmentioning

confidence: 99%

Efficiency and Target Derepression of Anti-miR-92a: Results of a First in Human Study

Abplanalp

Fischer

John

et al. 2020

Nucleic Acid Therapeutics

113

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MicroRNA (miRNA) inhibition is a promising therapeutic strategy in several disease indications. MRG-110 is a locked nucleic acid-based antisense oligonucleotide that targets miR-92a-3p and experimentally was shown to have documented therapeutic effects on cardiovascular disease and wound healing. To gain first insights into the activity of anti-miR-92a in humans, we investigated miR-92a-3p expression in several blood compartments and assessed the effect of MRG-110 on target derepression. Healthy adults were randomly assigned (5:2) to receive a single intravenous dose of MRG-110 or placebo in one of seven sequential ascending intravenous dose cohorts ranging from 0.01 to 1.5 mg/kg body weight. MiR-92a-3p whole blood levels were time and dose dependently decreased with halfmaximal inhibition of 0.27 and 0.31 mg/kg at 24 and 72 h after dosing, respectively. In the high-dose groups, >95% inhibition was detected at 24-72 h postinfusion and significant inhibition was observed for 2 weeks. Similar inhibitory effects were detected in isolated CD31 + cells, and miR-92a-3p expression was also inhibited in extracellular vesicles in the high-dose group. Target derepression was measured in whole blood and showed that ITGA5 and CD93 were increased at a dose of 1.5 mg/kg. Single-cell RNA sequencing of peripheral blood cells revealed a cell typespecific derepression of miR-92a targets. Together this study demonstrates that systemic infusion of anti-miR-92a efficiently inhibits miR-92a in the peripheral blood compartment and derepresses miR-92a targets in humans.

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REDD1 Is Essential for Optimal T Cell Proliferation and Survival

Cited by 27 publications

References 39 publications

Inhibition of REDD1 Sensitizes Bladder Urothelial Carcinoma to Paclitaxel by Inhibiting Autophagy

Inhibition of REDD1 Sensitizes Bladder Urothelial Carcinoma to Paclitaxel by Inhibiting Autophagy

REDD1 loss reprograms lipid metabolism to drive progression of RAS mutant tumors

Efficiency and Target Derepression of Anti-miR-92a: Results of a First in Human Study

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