Sestrin2: Its Potential Role and Regulatory Mechanism in Host Immune Response in Diseases

Wang, Lixue; Zhu, Xiaomei; Yao, Yong‐Ming

doi:10.3389/fimmu.2019.02797

Cited by 54 publications

(44 citation statements)

References 123 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although we did not confirmed the Sesn2 interaction with TRAF6 or p62 under RANKL-induced osteoclast differentiation, our results combined with previous reports suggest that Sesn2 promotes a strong interaction between TRAF6 and p62 and promotes RANKL-induced osteoclastogenesis via activations of NF-κB and MAPK downstream signaling pathways. In addition, to protect cells against endotoxicity, such as inflammation and aging, Sesn2 is activated by an increase in oxidative stress-induced Nrf2 and AP-1 via activation of toll-like receptors, by inhibition of ubiquitin-mediated Sestrin degradation, and by an increase in Sestrin-MAPK complexes in immune cells ( Wang et al, 2019 ; Kim et al, 2020 ). Further, it has been shown that p62 is highly expressed in osteoclasts in periapicitis and periodontitis models and that NOX4 is highly expressed in bones obtained from patients with osteoporosis and Paget disease, a focal disorder of enhanced bone remodeling ( Goettsch et al, 2013 ; Li et al, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Sestrin2 Regulates Osteoclastogenesis via the p62-TRAF6 Interaction

Kang

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

The receptor activator of nuclear factor-kappa B ligand (RANKL) mediates osteoclast differentiation and functions by inducing Ca2+ oscillations, activating mitogen-activated protein kinases (MAPKs), and activating nuclear factor of activated T-cells type c1 (NFATc1) via the RANK and tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) interaction. Reactive oxygen species (ROS) also plays an important role during osteoclastogenesis and Sestrin2, an antioxidant, maintains cellular homeostasis upon stress injury via regulation of ROS, autophagy, and inflammation. However, the role of Sestrin2 in osteoclastogenesis remains unknown. In this study, we investigated the role of Sestrin2 in the RANKL-RANK-TRAF6 signaling pathway during osteoclast differentiation. Deletion of Sestrin2 (Sesn2) increased bone mass and reduced the number of multinucleated osteoclasts on bone surfaces. RANKL-induced osteoclast differentiation and function decreased in Sesn2 knockout (KO) bone marrow-derived monocytes/macrophages (BMMs) due to inhibition of NFATc1 expression, but osteoblastogenesis was not affected. mRNA expression of RANKL-induced specific osteoclastogenic genes and MAPK protein expression were lower in Sesn2 KO BMMs than wild-type (WT) BMMs after RANKL treatment. However, the Sesn2 deletion did not affect ROS generation or intracellular Ca2+ oscillations during osteoclastogenesis. In contrast, the interaction between TRAF6 and p62 was reduced during osteoclasts differentiation in Sesn2 KO BMMs. The reduction in the TRAF6/p62 interaction and TRAP activity in osteoclastogenesis in Sesn2 KO BMMs was recovered to the WT level upon expression of Flag-Sesn2 in Sesn2 KO BMMs. These results suggest that Sestrin2 has a novel role in bone homeostasis and osteoclasts differentiation through regulation of NFATc1 and the TRAF6/p62 interaction.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Sesn2, an antioxidant, activates AMP-activated protein kinase (AMPK) and inhibits mTORC1 signaling. Sesn3 also suppresses mTORC1 activity and maintains Akt activity by activating the AMPK-TSC1/2 signaling axis ( Wang et al, 2019 ; Kim et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Sestrin2 Regulates Osteoclastogenesis via the p62-TRAF6 Interaction

Kang

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

show abstract

“…We also found that overexpression of SESN2 inhibited both expression of N-cadherin and activation of p70S6K. The anti-cancer effects of SESN2 are associated with regulation of the mTORC1 signaling pathway [ 58 , 59 ]. The mTOR signaling pathway is hyperactivated during carcinogenesis and tumor progression [ 60 ].…”

Section: Discussionmentioning

confidence: 99%

mTOR-Dependent Role of Sestrin2 in Regulating Tumor Progression of Human Endometrial Cancer

Shin

Bae

Park

et al. 2020

Cancers

View full text Add to dashboard Cite

Oncogenic activation of the mammalian target of rapamycin complex 1 (mTORC1) leads to endometrial cancer cell growth and proliferation. Sestrin2 (SESN2), a highly conserved stress-inducible protein, is involved in homeostatic regulation via inhibition of reactive oxygen species (ROS) and mTORC1. However, the role of SESN2 in human endometrial cancer remains to be investigated. Here, we investigated expression, clinical significance, and underlying mechanisms of SESN2 in endometrial cancer. SESN2 was upregulated more in endometrial cancer tissues than in normal endometrial tissues. Furthermore, upregulation of SESN2 statistically correlated with shorter overall survival and disease-free survival in patients with endometrial cancer. SESN2 expression strongly correlated with mTORC1 activity, suggesting its impact on prognosis in endometrial cancer. Additionally, knockdown of SESN2 promoted cell proliferation, migration, and ROS production in endometrial cancer cell lines HEC-1A and Ishikawa. Treatment of these cells with mTOR inhibitors reversed endometrial cancer cell proliferation, migration, and epithelial–mesenchymal transition (EMT) marker expression. Moreover, in a xenograft nude mice model, endometrial cancer growth increased by SESN2 knockdown. Thus, our study provides evidence for the prognostic significance of SESN2, and a relationship between SESN2, the mTORC1 pathway, and endometrial cancer growth, suggesting SESN2 as a potential therapeutic target in endometrial cancer.

show abstract

“…Sestrin2, a highly evolutionarily conserved protein, is involved in mediating cellular responses to various stressors. It has a protective effect against physiological and pathological conditions, mainly through regulating oxidative stress and inflammation [35]. Sestrin2 is a leucine sensor protein that regulates mTORC1 signaling that is related to cell proliferation and growth.…”

Section: Discussionmentioning

confidence: 99%

Sestrin2 Expression Has Regulatory Properties and Prognostic Value in Lung Cancer

Chae

Gil

Saha

et al. 2020

JPM

View full text Add to dashboard Cite

Lung cancer remains the most dangerous type of cancer despite recent progress in therapeutic modalities. Development of prognostic markers and therapeutic targets is necessary to enhance lung cancer patient survival. Sestrin family genes (Sestrin1, Sestrin2, and Sestrin3) are involved in protecting cells from stress. In particular, Sestrin2, which mainly protects cells from oxidative stress and acts as a leucine sensor protein in mammalian target of rapamycin (mTOR) signaling, is thought to affect various cancers in different ways. To investigate the role of Sestrin2 expression in lung cancer cells, we knocked down Sestrin2 in A549, a non-small cell lung cancer cell line; this resulted in reduced cell proliferation, migration, sphere formation, and drug resistance, suggesting that Sestrin2 is closely related to lung cancer progression. We analyzed Sestrin2 expression in human tissue using various bioinformatic databases and confirmed higher expression of Sestrin2 in lung cancer cells than in normal lung cells using Oncomine and the Human Protein Atlas. Moreover, analyses using Prognoscan and KMplotter showed that Sestrin2 expression is negatively correlated with the survival of lung cancer patients in multiple datasets. Co-expressed gene analysis revealed Sestrin2-regulated genes and possible associated pathways. Overall, these data suggest that Sestrin2 expression has prognostic value and that it is a possible therapeutic target in lung cancer.

show abstract

Sestrin2: Its Potential Role and Regulatory Mechanism in Host Immune Response in Diseases

Cited by 54 publications

References 123 publications

Sestrin2 Regulates Osteoclastogenesis via the p62-TRAF6 Interaction

Sestrin2 Regulates Osteoclastogenesis via the p62-TRAF6 Interaction

mTOR-Dependent Role of Sestrin2 in Regulating Tumor Progression of Human Endometrial Cancer

Sestrin2 Expression Has Regulatory Properties and Prognostic Value in Lung Cancer

Contact Info

Product

Resources

About