Involvement of TGF-β1/Smad3 Signaling in Carbon Tetrachloride-Induced Acute Liver Injury in Mice

Niu, Liman; Cui, Xueling; Qi, Yan; Xie, Dongxue; Wu, Qian; Chen, Xinxin; Ge, Jingyan; Liu, Zhonghui

doi:10.1371/journal.pone.0156090

Cited by 41 publications

(39 citation statements)

References 40 publications

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“…Furthermore, Bax overexpression did not exert a direct negative effect on Smad3 binding to SBEs for regulation of the AMTN gene. The mechanism of physical interaction between Smad3 and Bax is unknown, although it has been reported that Smad3 overexpression promotes the expression of apoptosis-related Bax mRNA in hepatocytes (37). As we found that Bax expression induced Smad3 expression in the nucleus and cytosol (Fig.…”

Section: Discussionsupporting

confidence: 60%

TGFβ1-induced Amelotin gene expression is downregulated by Bax expression in mouse gingival epithelial cells

et al. 2018

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Amelotin (AMTN) is induced upon initiation of apoptosis by transforming growth factor beta1 (TGFβ1) and is mediated by Smad3 in gingival epithelial cells (GE1 cells). This upregulation of AMTN gene expression is temporary, and the mechanism responsible is still unclear. The present study investigated the transcriptional downregulation of TGFβ1-induced AMTN gene expression in GE1 cells during the progression of apoptosis. To examine time-dependent changes in the levels of AMTN, Smad3 and Bax mRNA induced by TGFβ1, real-time PCR analyses were performed. Immunocytochemistry was carried out to detect the expression of Smad3 and Bax. Transient transfection analyses were performed using mouse AMTN gene promoter constructs of various lengths including Smad response elements (SBEs), in the presence or absence of TGFβ1. Changes in Smad3 binding to SBEs resulting from overexpression of Bax were examined using ChIP assays. Overexpression of Bax dramatically downregulated the levels of TGFβ1-induced AMTN mRNA and transcription of the AMTN gene. Smad3 binding to SBEs in the mouse AMTN gene promoter was induced by overexpression of Smad3 or TGFβ1, and this was inhibited by Bax overexpression. These results show that the levels of AMTN mRNA induced by TGFβ1 and Smad3 are decreased by robust expression of Bax in gingival epithelial cells.

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Section: Discussionsupporting

confidence: 60%

TGFβ1-induced Amelotin gene expression is downregulated by Bax expression in mouse gingival epithelial cells

et al. 2018

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“…Activin A initially binds to activin type II receptors (ActRII), and then recruits activin type I receptors to phosphorylate and activate SMAD family member (Smad) 2/3 in the cytoplasm, with this being the common signaling molecule between activin and TGF-β (6). The activated Smad2/3 forms a complex with Smad4 and then the complex is translocated into the nucleus, resulting in downstream target gene transcription to elicit biological effects, including cell differentiation, proliferation and apoptosis (7,8).…”

Section: Introductionmentioning

confidence: 99%

Activin A induces apoptosis of mouse myeloma cells via the mitochondrial pathway

Zhang

Zhao

et al. 2017

Oncol Lett

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Abstract. Activin A is a pleiotropic cytokine belonging to the transforming growth factor β superfamily. Abnormal expression of activin A is associated with tumorigenesis. Multiple myeloma is characterized by the development of osteolytic disease, which ultimately leads to cachexia. However, the involvement of activin A in myeloma cell viability and apoptosis remains to be fully elucidated. For this purpose, mouse myeloma NS-1 cells were treated with activin A, and subsequently subjected to 5-bromo-2'-deoxyuridine analysis, Hoechst 33342 staining, flow cytometry and western blot analysis. The results revealed that activin A significantly suppressed NS-1 cell viability, and induced NS-1 cell apoptosis. In addition, activin A-induced promotion of NS-1 cell apoptosis was accompanied by upregulated expression of BCL2 associated X, apoptosis regulator (Bax), but downregulated expression of B cell lymphoma-2 (Bcl-2), resulting in an increase of the Bax/Bcl-2 ratio. Furthermore, cytochrome c and caspase-3 protein expression also increased following treatment with activin A. These data suggest that activin A induces apoptosis in mouse myeloma NS-1 cells via the mitochondrial pathway, providing a novel insight into multiple myeloma treatment.

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“…Thus, LXRα and TGF‐β may act against each other in an antagonistic manner for hepatocyte viability, supportive of the loop pathway between LXRα and TGF‐β. It has also been shown that TGF‐β was elevated in mice treated with CCl 4 or APAP and in patients with acute liver failure . Given the lack of information on the role of TGF‐β signaling in toxicant‐induced liver injury, we additionally performed an experiment using SB525334, an inhibitor of TβRI, and found that SB525334 treatment ameliorated CCl 4 ‐induced liver injury, as shown by decreases in serum ALT activity and hepatic Bax mRNA level (Supporting Fig.…”

Section: Discussionmentioning

confidence: 97%

Liver X Receptor α–Induced Cannabinoid Receptor 2 Inhibits Ubiquitin‐Specific Peptidase 4 Through miR‐27b, Protecting Hepatocytes From TGF‐β

Kim

et al. 2019

Hepatol Commun

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Liver X receptor‐alpha (LXRα) acts as a double‐edged sword in different biological situations. Given the elusive role of LXRα in hepatocyte viability, this study investigated whether LXRα protects hepatocytes from injurious stimuli and the underlying basis. LXRα activation prevented hepatocyte apoptosis from CCl4 challenges in mice. Consistently, LXRα protected hepatocytes specifically from transforming growth factor‐beta (TGF‐β), whereas LXRα deficiency aggravated TGF‐β‐induced hepatocyte injury. In the Gene Expression Omnibus database analysis for LXR−/− mice, TGF‐β receptors were placed in the core network. Hierarchical clustering and correlation analyses enabled us to find cannabinoid receptor 2 (CB2) as a gene relevant to LXRα. In human fibrotic liver samples, both LXRα and CB2 were lower in patients with septal fibrosis and cirrhosis than those with portal fibrosis. LXRα transcriptionally induced CB2; CB2 then defended hepatocytes from TGF‐β. In a macrophage depletion model, JWH133 (a CB2 agonist) treatment prevented toxicant‐induced liver injury. MicroRNA 27b (miR‐27b) was identified as an inhibitor of ubiquitin‐specific peptidase 4 (USP4), deubiquitylating TGF‐β receptor 1 (TβRI), downstream from CB2. Liver‐specific overexpression of LXRα protected hepatocytes from injurious stimuli and attenuated hepatic inflammation and fibrosis. Conclusion: LXRα exerts a cytoprotective effect against TGF‐β by transcriptionally regulating the CB2 gene in hepatocytes, and CB2 then inhibits USP4‐stabilizing TβRI through miR‐27b. Our data provide targets for the treatment of acute liver injury.

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Involvement of TGF-β1/Smad3 Signaling in Carbon Tetrachloride-Induced Acute Liver Injury in Mice

Cited by 41 publications

References 40 publications

TGFβ1-induced Amelotin gene expression is downregulated by Bax expression in mouse gingival epithelial cells

TGFβ1-induced Amelotin gene expression is downregulated by Bax expression in mouse gingival epithelial cells

Activin A induces apoptosis of mouse myeloma cells via the mitochondrial pathway

Liver X Receptor α–Induced Cannabinoid Receptor 2 Inhibits Ubiquitin‐Specific Peptidase 4 Through miR‐27b, Protecting Hepatocytes From TGF‐β

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