Sestrin2: A Promising Therapeutic Target for Liver Diseases

Kim, Kyu Min; Yang, Ji Hye; Shin, Sook; Cho, Il Je; Ki, Sung Hwan

doi:10.1248/bpb.b15-00228

Cited by 24 publications

(16 citation statements)

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“…Much attention has been paid to investigate the function of Sesns in diverse liver injuries and metabolism disorders [12, 36, 37]. The results about the expression of Sesns in high-fat diet induced disease models were inconsistent.…”

Section: Sesns In Liver and Metabolismmentioning

confidence: 99%

Recent Insights into the Biological Functions of Sestrins in Health and Disease

Wang

Liu

et al. 2017

Cell Physiol Biochem

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Sestrins (Sesns) have been identified as a family of highly conserved stress-inducible proteins that are strongly up-regulated by various stresses, including DNA damage, oxidative stress, and hypoxia. The Sesns play protective roles in most physiological and pathological conditions mainly through the regulation of oxidative stress, inflammation, autophagy, endoplasmic reticulum stress, and metabolic homeostasis. In this review, we discussed the possible regulators of Sesns expression, such as p53, forkhead box O, nuclear factor erythroid 2 like 2 (Nrf2), NH (2)-terminal kinase (JNK)/c-Jun pathway and hypoxia-inducible factor-1α (Hif-1α), and the downstream pathways regulated by the Sesns including AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) signaling, mitogen-activated protein kinases (MAPKs) signaling, Nrf2 signaling, NADPH oxidase signaling and transforming growth factor β (TGF-β) signaling in heart diseases, lung diseases, gastrointestinal tract diseases, liver and metabolism diseases, neurological diseases, kidney diseases and immunological diseases. This review aims to provide a comprehensive understanding the protective effects of Sesns.

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Section: Sesns In Liver and Metabolismmentioning

confidence: 99%

Recent Insights into the Biological Functions of Sestrins in Health and Disease

Wang

Liu

et al. 2017

Cell Physiol Biochem

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“…SESN2 is an anti-oxidant protein evolutionally conserved in various species and is inducible by oxidative, genotoxic and energetic stress [ 31 ]. SESN2 can reduce cysteine formed a sulfinic acid of peroxiredoxins (Prxs), which is unreducible by the thioredoxin system [ 32 ].…”

Section: Introductionmentioning

confidence: 99%

Arsenic trioxide-mediated suppression of miR-182-5p is associated with potent anti-oxidant effects through up-regulation ofSESN2

et al. 2018

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Arsenic trioxide (ATO) is a traditional Chinese medicine that can induce oxidative stress for treatment of cancer cells. However, ATO may generate anti-oxidative responses to compromise the cytotoxic effect, but the underlying mechanisms remain unclear. Here we found that ATO could inhibit miR-182-5p expression in patient-derived primary S1 glioblastoma (GBM) cells accompanied by up-regulation of Sestrin-2 (SESN2) mRNA, a known anti-oxidant molecule. This phenomenon was also detected in a U87MG glioma cell line, human lung adenocarcinoma H1299 cell line and A549 cell line. Pretreatment with a free radical scavenger N-acetylcysteine (NAC) reduced the oxidative stress induced by ATO. Concomitantly, ATO mediated suppression of miR-182-5p and enhancement of SESN2 expression were also compromised. The MTT assay further showed that ATO induced cytotoxicity was enhanced by transfection of miR-182-5p mimics. Overexpression of miR-182-5p mimics significantly suppressed the expression of SENS2 and a firefly luciferase reporter gene fused to 3’- untranslated region (UTR) of SESN2 mRNA. Use of ribonucleoprotein immunoprecipitation (RNP-IP), ATO mediated suppression of miR-182-5p led to the stabilization of SESN2 mRNA as a result of Argonaute-2 (AGO2) dependent gene silencing. Furthermore, high expression of miR-182-5p and low expression of SESN2 mRNA tend to be associated with longer survival of glioma or lung cancer patients using public available gene expression datasets and online tools for prediction of clinical outcomes. Taken together, current data suggest that the miR-182-5p/SENS2 pathway is involved in ATO induced anti-oxidant responses, which may be important for the design of novel strategy for cancer treatment.

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“…Interestingly, Sestrin2 gene expression was reported to be controlled by NF-E2-related factor-2 (Nrf2), a redox-sensitive transcription factor that is critical in the expression of various antioxidant genes [22], which is also upregulated by T 3 administration as a mechanism affording protection against oxidative stress [23]. Due to its antioxidant behaviour and the control of metabolic functions leading to mitohormesis, Sestrin2 was proposed as a promising therapeutic target to prevent or treat liver diseases [24][25][26].…”

Section: Resultsmentioning

confidence: 99%

Thyroid Hormone-Induced Expression of the Hepatic Scaffold Proteins Sestrin2, β-Klotho, and FRS2α in Relation to FGF21-AMPK Signaling

Videla

Vargas

Riquelme

et al. 2017

Exp Clin Endocrinol Diabetes

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Thyroid hormone (3,3',5-triiodothyronine, T) accelerates energy metabolism in the liver through mechanisms involving upregulation of AMP-activated protein kinase (AMPK). This study aims to assess the influence of T on the expression of the scaffold proteins β-Klotho, fibroblast growth factor receptor substrate 2α (FRS2α), and Sestrin2 in relation to FGF21-AMPK signaling. Male Sprague-Dawley rats were given 0.1 mg T/kg or hormone vehicle (controls) and studies were done 24 h after treatment. These include measurements of the mRNA expression (qPCR) of hepatic β-Klotho, FGF21, FGF21 receptor-1 (FGFR1), extracellular-signal-regulated kinase 1/2 (ERK1/2), FRS2α, ribosomal S6 kinase-1 (RSK1), liver kinase B1 (LKB1), AMPK, and Sestrin2. Also, protein levels of FGF21, FGFR1 (ELISA), and ERK1/2 (Western blot) were measured. T elicited a calorigenic response with higher hepatic mRNA expression of β-Klotho, FRS2α, and FGF21, increased serum FGF21, without changes in liver FGFR1 mRNA and its plasma levels. In addition, T enhanced ERK1/2 phosphorylation and the mRNA expression of ERK1/2, RSK1, LKB1, AMPK, and Sestrin2. T administration enhances liver FGF21-AMPK signaling involving upregulation of the scaffold proteins β-Klotho, FRS2α, and Sestrin2. β-Klotho and FRS2 induction favours the operation of the FGF21-FGFR1-β-Klotho complex as evidenced by the enhancement in ERK1/2 phosphorylation, whereas that of Sestrin2 recruits LKB1 to achieved AMPK activation, thus supporting a higher energy expenditure condition that may be desirable in some metabolic disorders.

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Sestrin2: A Promising Therapeutic Target for Liver Diseases

Cited by 24 publications

References 50 publications

Recent Insights into the Biological Functions of Sestrins in Health and Disease

Recent Insights into the Biological Functions of Sestrins in Health and Disease

Arsenic trioxide-mediated suppression of miR-182-5p is associated with potent anti-oxidant effects through up-regulation ofSESN2

Thyroid Hormone-Induced Expression of the Hepatic Scaffold Proteins Sestrin2, β-Klotho, and FRS2α in Relation to FGF21-AMPK Signaling

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