Tonicity-Responsive Enhancer-Binding Protein Mediates Hyperglycemia-Induced Inflammation and Vascular and Renal Injury

Choi, Soo Youn; Lim, Sun Woo; Salimi, Saeedeh; Yoo, Eun Jin; Lee-Kwon, Whaseon; Lee, Hwan Hee; Lee, Jun Ho; Mitchell, Braxton D.; Sanada, Satoshi; Parsa, Afshin; Kwon, Hyug Moo

doi:10.1681/asn.2017070718

Cited by 34 publications

(35 citation statements)

References 47 publications

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“…TonEBP is a central component of the NF-κB enhanceosome assembled on promoters of inflammatory genes [19] . TonEBP expression is stimulated by inflammation leading to elevated expression of pro-inflammatory genes and chronic inflammatory diseases [ [20] , [21] , [22] , [23] , [24] ]. In addition, TonEBP is recruited to the sites of DNA damage as an upstream regulator of DDR [25] .…”

Section: Introductionmentioning

confidence: 99%

Tonicity-responsive enhancer-binding protein promotes stemness of liver cancer and cisplatin resistance

et al. 2020

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Background High recurrence and chemoresistance drive the high mortality in hepatocellular carcinoma (HCC). Although cancer stem cells are considered to be the source of recurrent and chemoresistant tumors, they remain poorly defined in HCC. Tonicity-responsive enhancer binding protein (TonEBP) is elevated in almost all HCC tumors and associated with recurrence and death. We aimed to identify function of TonEBP in stemness and chemoresistance of liver cancer. Methods Tumors obtained from 280 HCC patients were analyzed by immunohistochemical analyses. Stemness and chemoresistance of liver CSCs (LCSCs) were investigated using cell culture. Tumor-initiating activity was measured by implanting LCSCs into BALB/c nude mice. Findings Expression of TonEBP is higher in LCSCs in HCC cell lines and correlated with markers of LCSCs whose expression is significantly associated with poor prognosis of HCC patients. TonEBP mediates ATM-mediated activation of NF-κB, which stimulates the promoter of a key stem cell transcription factor SOX2. As expected, TonEBP is required for the tumorigenesis and self-renewal of LSCSs. Cisplatin induces the recruitment of the ERCC1/XPF dimer to the chromatin in a TonEBP-dependent manner leading to DNA repair and cisplatin resistance. The cisplatin-induced inflammation in LSCSs is also dependent on the TonEBP-ERCC1/XPF complex, and leads to enhanced stemness via the ATM-NF-κB-SOX2 pathway. In HCC patients, tumor expression of ERCC1/XPF predicts recurrence and death in a TonEBP-dependent manner. Interpretation TonEBP promotes stemness and cisplatin resistance of HCC via ATM-NF-κB. TonEBP is a key regulator of LCSCs and a promising therapeutic target for HCC and its recurrence.

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Section: Introductionmentioning

confidence: 99%

Tonicity-responsive enhancer-binding protein promotes stemness of liver cancer and cisplatin resistance

et al. 2020

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“…The primary finding of this study is that TonEBP protects β-cells against ER stress. Although TonEBP has both protective and pathological effects in a stress- and cell type-dependent manner, the interpretation of this result is complicated by the previous findings that islet autoimmunity in humans is associated with an increased expression of TonEBP [ 23 ] and that the blood glucose level in mice with global TonEBP haplo-deficiencies is comparable with that in their wild-type littermates [ 79 ]. However, there is a possible explanation for these discrepant findings.…”

Section: Discussionmentioning

confidence: 99%

TonEBP Promotes β-Cell Survival under ER Stress by Enhancing Autophagy

Kang

Yoo

Lee

et al. 2020

Cells

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The endoplasmic reticulum (ER) stress response and autophagy are important cellular responses that determine cell fate and whose dysregulation is implicated in the perturbation of homeostasis and diseases. Tonicity-responsive enhancer-binding protein (TonEBP, also called NFAT5) is a pleiotropic stress protein that mediates both protective and pathological cellular responses. Here, we examined the role of TonEBP in β-cell survival under ER stress. We found that TonEBP increases β-cell survival under ER stress by enhancing autophagy. The level of TonEBP protein increased under ER stress due to a reduction in its degradation via the ubiquitin–proteasome pathway. In response to ER stress, TonEBP increased autophagosome formations and suppressed the accumulation of protein aggregates and β-cell death. The Rel-homology domain of TonEBP interacted with FIP200, which is essential for the initiation of autophagy, and was required for autophagy and cell survival upon exposure to ER stress. Mice in which TonEBP was specifically deleted in pancreatic endocrine progenitor cells exhibited defective glucose homeostasis and a loss of islet mass. Taken together, these findings demonstrate that TonEBP protects against ER stress-induced β-cell death by enhancing autophagy.

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“…Mice were kept on a 12-h light/dark cycle with free access to standard chow and water. Peritoneal macrophages (PMs) were isolated from our previously developed mouse model of type 1 diabetes (35). Briefly, males were selected and made diabetic by daily intraperitoneal injections of freshly prepared streptozotocin (STZ) (50 mg/kg body weight; Sigma-Aldrich, St. Louis, MO) in 0.1 M citrate buffer (pH 4.5) for 4 days.…”

Section: Methodsmentioning

confidence: 99%

TonEBP Suppresses the HO-1 Gene by Blocking Recruitment of Nrf2 to Its Promoter

Yoo

Lee

et al. 2019

Front. Immunol.

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TonEBP is a key transcriptional activator in macrophages with an M1 phenotype. High expression of TonEBP is associated with many inflammatory diseases. Heme oxygenase-1 (HO-1), a stress-inducible protein, is induced by various oxidative and inflammatory signals, and its expression is regarded as an adaptive cellular response to inflammation and oxidative injury. Here, we show that TonEBP suppresses expression of HO-1 by blocking Nrf2 binding to the HO-1 promoter, thereby inducing polarization of macrophages to the M1 phenotype. Inhibition of HO-1 expression or activity significantly reduced the inhibitory responses on M1 phenotype and stimulatory effects on M2 phenotype by TonEBP knockdown. Additional experiments showed that HO-1 plays a role in the paracrine anti-inflammatory effects of TonEBP knockdown in macrophages. Identification of HO-1 as a downstream effector of TonEBP provides new possibilities for improved therapeutic approaches to inflammatory diseases.

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Tonicity-Responsive Enhancer-Binding Protein Mediates Hyperglycemia-Induced Inflammation and Vascular and Renal Injury

Cited by 34 publications

References 47 publications

Tonicity-responsive enhancer-binding protein promotes stemness of liver cancer and cisplatin resistance

Tonicity-responsive enhancer-binding protein promotes stemness of liver cancer and cisplatin resistance

TonEBP Promotes β-Cell Survival under ER Stress by Enhancing Autophagy

TonEBP Suppresses the HO-1 Gene by Blocking Recruitment of Nrf2 to Its Promoter

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