SOD1 Phosphorylation by mTORC1 Couples Nutrient Sensing and Redox Regulation

Tsang, Chi Kwan; Chen, Miao; Cheng, Xin; Qi, Yanmei; Chen, Yin; Das, Indrajit; Li, Xiaoxing; Vallat, Brinda; Li, Fu; Qian, Chao Nan; Wang, Hui Yun; White, Eileen; Burley, S.K.; Zheng, Xi

doi:10.1016/j.molcel.2018.03.029

Cited by 91 publications

(94 citation statements)

References 59 publications

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“…The animal protocol was approved by the Animal Ethics Committee of Sun Yat-Sen University Cancer Center. Subcutaneous xenograft models were established, and drug treatments were carried out as previously described (21)(22)(23)(24)(25). Four-week-old female BALB/c nude mice were used in this study.…”

Section: In Vivo Studies and Ihcmentioning

confidence: 99%

Sorafenib and Carfilzomib Synergistically Inhibit the Proliferation, Survival, and Metastasis of Hepatocellular Carcinoma

Jiang

et al. 2018

Molecular Cancer Therapeutics

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Hepatocellular carcinoma (HCC) is one of the most common and deadly human cancers. The 5-year survival rate is very low. Unfortunately, there are few efficacious therapeutic options. Until recently, Sorafenib has been the only available systemic drug for advanced HCC. However, it has very limited survival benefits, and new therapies are urgently needed. In this study, we investigated the anti-HCC activity of carfilzomib, a second-generation, irreversible proteasome inhibitor, as a single agent and in combination with sorafenib. , we found that carfilzomib has moderate anticancer activity toward liver cancer cells, but strongly enhances the ability of sorafenib to suppress HCC cell growth, proliferation, migration, invasion, and survival. Remarkably, the drug combination exhibits even more potent antitumor activity when tested in animal tumor models. Mechanistically, the combined treatment activates caspase-dependent and endoplasmic reticulum stress/CHOP-mediated apoptotic pathways, and suppresses epithelial-mesenchymal transition. In conclusion, our results demonstrate that the combination of carfilzomib and sorafenib has synergistic antitumor activities against HCC, providing a potential therapeutic strategy to improve the mortality and morbidity of HCC patients.

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Section: In Vivo Studies and Ihcmentioning

confidence: 99%

Sorafenib and Carfilzomib Synergistically Inhibit the Proliferation, Survival, and Metastasis of Hepatocellular Carcinoma

Jiang

et al. 2018

Molecular Cancer Therapeutics

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“…Ace and Slc12a) expressed at the other end of the spectrum ( Figure 5B), with a clear correspondence to real developmental time ( Figure 5C). Pseudotime analysis indicated that cells with an early phenotype upregulated Ly6C 47 , a gene expressed by classical monocytes, and genes associated with the cytoskeleton (Actb, Vim) 48,49 , matrix remodeling (Fn1, F13a1, Vcan) 50,51 , and reduction-oxidation (Sod1, Prdx6) 52,53 in keeping with the marked physiological changes and rapid remodeling occurring in the lung during the fetal-neonatal transition ( Figure 5D and E). Over both pseudoand real time, this gene expression pattern evolved into an immunomodulatory signature, reflected by the up-regulation of genes associated with macrophage differentiation (Csf1, Spn) 54 , macrophage polarization (Tgm2, Cd36) 55 , negative regulation of inflammation (Ceacam1, Ear2, Lair1) 56 , and innate immunity (Cd300ld, Treml4) 57 .…”

Section: Mac V Monocytes Are Characterized By Developmental Gene Exprmentioning

confidence: 61%

Diverse homeostatic and immunomodulatory roles of immune cells in the developing mouse lung revealed at single cell resolution

Domingo-Gonzalez

Zanini

Che

et al. 2020

Preprint

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22At birth, the lungs experience a sudden transition from a pathogen-free, hypoxic, fluid-23 filled environment to a pathogen-rich, rhythmically distended air-liquid interface. While many 24 studies focus on adult tissue, the heterogeneity of immune cells in the perinatal lung remains 25 unexplored. Here, we combine single cell transcriptomics with in situ hybridization to present an 26 atlas of the murine lung immune compartment during a critical period of lung development. We 27show that the late embryonic lung is dominated by specialized proliferative macrophages with a 28 surprising physical interaction with the developing vasculature. These macrophages disappear 29 after birth and are replaced by a complex and dynamic mixture of macrophage subtypes, dendritic 30 cells, granulocytes, and lymphocytes. Detailed characterization of macrophage diversity revealed 31 a precise orchestration of five distinct subpopulations across postnatal development to fill context-32 specific functions in tissue remodeling, angiogenesis, and immunity. These data both broaden the 33 putative roles for immune cells in the developing lung and provide a framework for understanding 34 how external insults alter immune cell phenotype during a period of rapid lung growth and 35 heightened vulnerability. 36 37Immune cells play a central role in the development of many organs. Innate and adaptive 52 immune cells regulate epithelial architecture during mammary gland development by promoting 53 terminal end bud elongation and impairing ductal invasion 5 . Lymphocytes play a key role in 54 oligodendrogenesis and synapse formation 6 , and macrophages inform kidney 7 , brain 8 , and retina 9 55 organogenesis. In highly vascularized organs, macrophages localize to the tips of vascular sprouts 56 to enhance vascular network complexity 9 , promote angiogenesis 10 , and regulate vascular 57 patterning 11 . Although proximal lung branching occurs during early gestation, the development of 58 distal airspaces capable of gas exchange begins only just before birth during the saccular stage of 59 development. These saccules are subsequently divided into millions of alveoli after birth during 60 alveolarization, the final stage of development characterized by rapid lung parenchymal and 61 vascular growth 12 . Whether temporal regulation of specific immune populations informs lung 62 immune function or the significant pulmonary parenchymal and vascular growth and remodeling 63 occurring during early postnatal life remains unknown. 64The prevailing notion is that the neonatal immune compartment is immature 13 . Limited 65 immune competence, including attenuated innate immunity 14 , poor immuno-stimulatory function 66 of antigen presenting cells 15 , and skewed adaptive immune responses may underlie the heightened 67 susceptibility of infants to viral and bacterial infections 13 . Although the neonatal immune system 68 can be induced to manifest adult-like responses under certain conditions 16 , this type-2-skewed 69 immune environment likely facilitates i...

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“…Zhao et al, 2015;Rousseau et al, 2016;5. Sun et al, 2012;Tsang et al, 2018;6. Gomez-Suaga et al, 2017;Zhao et al, 2018;7.…”

Section: Cunclassified

SOD1 activity thresholds and TOR signalling modulate VAP(P58S) aggregation via ROS-induced proteasomal degradation in a Drosophila model of Amyotrophic Lateral Sclerosis

Chaplot

Pimpale

Ramalingam

et al. 2018

Preprint

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Familial Amyotrophic Lateral Sclerosis (F-ALS) is an incurable, late onset motor neuron disease, linked strongly to various causative genetic loci. ALS8 codes for a missense mutation, P56S, in VAMP-associated Protein B (VAPB) that causes the protein to misfold and form cellular aggregates. Uncovering genes and mechanisms that affect aggregation dynamics would greatly help increase our understanding of the disease and lead to potential therapeutics.Here, we develop a quantitative high-throughput, Drosophila S2R+ cell-based kinetic assay coupled with fluorescent microscopy to score for genes involved in the modulation of aggregates of fly ortholog, VAP(P58S), tagged with GFP. As proof of principle, we conducted a targeted RNAi screen against 900 genes, consisting of VAP genetic interactors, other ALS loci, as also genes involved in proteostasis. The screen identified 150 hits that modify aggregation, including the ALS loci SOD1, TDP43 and also genes belonging to the TOR pathway.To validate these modifiers, we developed a system to measure the extent of VAP(P58S) aggregation in the Drosophila third instar larval brain using the UAS-GAL4 system, followed by quantitative imaging of cellular inclusions. We find that reduction of SOD1 activity or decreased TOR signalling reduces aggregation. Interestingly, we find that increase in cellular reactive oxygen species (ROS) levels, assessed by measuring oxidation of cellular lipids and proteins, in response to SOD1 knockdown or by inhibition of TOR signalling appears to be the trigger for clearing of aggregates. The mechanism of aggregate clearance is, primarily, the proteasomal machinery, and not autophagy. Increase in VAP, but not VAP(P58S) levels, appears to elevate ROS, which may in turn regulate VAP transcription in a feedback loop.We have thus uncovered an interesting interplay between SOD1, ROS and TOR signalling that regulates the dynamics of VAP aggregation. Mechanistic processes underlying such cellular regulatory networks will lead us to a better understanding of initiation and progression of ALS.

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SOD1 Phosphorylation by mTORC1 Couples Nutrient Sensing and Redox Regulation

Cited by 91 publications

References 59 publications

Sorafenib and Carfilzomib Synergistically Inhibit the Proliferation, Survival, and Metastasis of Hepatocellular Carcinoma

Sorafenib and Carfilzomib Synergistically Inhibit the Proliferation, Survival, and Metastasis of Hepatocellular Carcinoma

Diverse homeostatic and immunomodulatory roles of immune cells in the developing mouse lung revealed at single cell resolution

SOD1 activity thresholds and TOR signalling modulate VAP(P58S) aggregation via ROS-induced proteasomal degradation in a Drosophila model of Amyotrophic Lateral Sclerosis

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