Hepatic Deletion of Smad7 in Mouse Leads to Spontaneous Liver Dysfunction and Aggravates Alcoholic Liver Injury

Zhu, Lu; Wang, Lingdi; Xiao, Wang; Luo, Xiaolin; Yang, Ling; Zhang, Rui; Yin, Hongkun; Xie, Dong; Pan, Yi; Chen, Yan

doi:10.1371/journal.pone.0017415

Cited by 29 publications

(29 citation statements)

References 38 publications

(57 reference statements)

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“…Furthermore, we revealed that Smad7 also down‐regulated TGF β activity in HCC (Figure A). This finding is in line with recent studies reporting the functional roles of Smad7 in liver diseases, that over‐expression of Smad7 in mouse liver attenuates TGF β signalling, reduces TGF β ‐mediated fibrogenesis and protects against liver damage , while functional loss of Smad7 in liver is associated with over‐expression of TGF β , hyperactivity of TGF β signalling and enhanced liver damage and fibrosis . Using HCCs from WT and Smad7 KO mice, we demonstrated the down‐regulation of TGF β protein and reduced activity of Smad3 in Smad7 WT mice (Figure B).…”

Section: Discussionsupporting

confidence: 91%

“…DEN‐induced hepatocarcinogenesis was chosen because its global gene expression patterns are most similar to those of human HCC . Using this DEN‐induced HCC model, we demonstrated for the first time that the deletion of Smad7 significantly enhanced hepatocarcinogenesis in vivo , which is in accord with recent findings that loss of endogenous Smad7 in mice leads to spontaneous liver dysfunction, ethanol‐induced liver injury, CCl4‐induced liver damage and hepatic fibrosis . These findings suggest that Smad7 may play a tumour suppressor role in hepatocarcinogenesis.…”

Section: Discussionsupporting

confidence: 86%

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Inhibitory role of Smad7 in hepatocarcinogenesis in mice and in vitro

Wang

Zhao

Chu

et al. 2013

The Journal of Pathology

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Smad7 is a principal inhibitor of the TGFβ-Smad signalling pathway. We have investigated the functional significance of Smad7 in hepatocellular carcinoma (HCC). Smad7 knockout (KO) and wild-type (WT) mice were injected with diethylnitrosamine (DEN) to induce HCC. The effects of Smad7 on cellular features were examined in HCC cells, using a Smad7 over-expression or deletion approach. Signalling pathway components modulated by Smad7 in HCC were evaluated using luciferase reporter assay and co-immunoprecipitation. Smad7 was down-regulated in human HCCs compared with the adjacent normal tissues (p < 0.001). Smad7 KO mice were more susceptible to DEN-induced HCC than WT mice (78% versus 22%, p < 0.05). HCCs from KO mice displayed a greater proliferation activity (p < 0.05) and a reduced apoptotic index compared with WT littermates (p < 0.05). Deletion of Smad7 promoted cell proliferation in primary cultured HCC cells. In addition, over-expression of Smad7 in HCC cell lines markedly suppressed cell growth (p < 0.0001) and colony formation (p < 0.01). Cell cycle analysis revealed an increase in the G1 phase and a reduction in the S-phase populations, accompanied by up-regulation of p27(Kip1) and down-regulation of cyclin D1. Smad7 increased cell apoptosis (p < 0.01) by mediating an intrinsic [caspase-9, caspase-3 and poly(ADP-ribose) polymerase] apoptotic pathway. Moreover, Smad7 inhibited NF-κB signalling by interacting with TAB2, an upstream activator of NF-κB, and inhibited TGFβ signalling by suppressing phosphorylation of Smad3. In conclusion, loss of Smad7 enhances susceptibility to HCC. Smad7 suppresses HCC cell growth by inhibiting proliferation and G1 -S phase transition and inducing apoptosis through attenuation of NF-κB and TGFβ signalling. Smad7 acts as a potential tumour suppressor in liver.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 86%

Inhibitory role of Smad7 in hepatocarcinogenesis in mice and in vitro

Wang

Zhao

Chu

et al. 2013

The Journal of Pathology

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“…Furthermore, Smad7 also promotes liver-specific metastasis of the colorectal tumor cells; this is correlated with active but subverted TGFβ signaling in the metastatic lesions (Halder et al 2008). Interestingly, studies of a mouse model with liver-specific knockout of the Smad7 gene have revealed that these otherwise healthy mice exhibit liver dysfunction and are prone to alcohol-induced tissue fibrosis, whereas exposure to TGFβ leads to accelerated EMT in the knockout hepatocytes (Zhu et al 2011). …”

Section: Switch Of Tgfβ Signaling From Tumor Suppression To Tumor Promentioning

confidence: 99%

Role of Smads in TGFβ signaling

2011

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Transforming growth factor-β (TGFβ) is the prototype for a large family of pleiotropic factors that signal via heterotetrameric complexes of type I and type II serine/threonine kinase receptors. Important intracellular mediators of TGFβ signaling are members of the Smad family. Smad2 and 3 are activated by C-terminal receptor-mediated phosphorylation, whereafter they form complexes with Smad4 and are translocated to the nucleus where they, in cooperation with other transcription factors, co-activators and co-repressors, regulate the transcription of specific genes. Smads have key roles in exerting TGFβ-induced programs leading to cell growth arrest and epithelial-mesenchymal transition. The activity and stability of Smad molecules are carefully regulated by a plethora of post-translational modifications, including phosphorylation, ubiquitination, sumoylation, acetylation and poly(ADP)-ribosylation. The Smad function has been shown to be perturbed in certain diseases such as cancer.

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“…The immunoblotting assay was described previously (23). The mouse antitubulin antibody was from Sigma-Aldrich.…”

Section: Immunoblotting Analysismentioning

confidence: 99%

Regulation of Glucose Homeostasis and Lipid Metabolism by PPP1R3G-mediated Hepatic Glycogenesis

Zhang

Huang

et al. 2014

Molecular Endocrinology

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Liver glycogen metabolism plays an important role in glucose homeostasis. Glycogen synthesis is mainly regulated by glycogen synthase that is dephosphorylated and activated by protein phosphatase 1 (PP1) in combination with glycogen-targeting subunits or G subunits. There are seven G subunits (PPP1R3A to G) that control glycogenesis in different organs. PPP1R3G is a recently discovered G subunit whose expression is changed along the fasting-feeding cycle and is proposed to play a role in postprandial glucose homeostasis. In this study, we analyzed the physiological function of PPP1R3G using a mouse model with liver-specific overexpression of PPP1R3G. PPP1R3G overexpression increases hepatic glycogen accumulation, stimulates glycogen synthase activity, elevates fasting blood glucose level, and accelerates postprandial blood glucose clearance. In addition, the transgenic mice have a reduced fat composition, together with decreased hepatic triglyceride level. Fasting-induced hepatic steatosis is relieved by PPP1R3G overexpression. In addition, PPP1R3G overexpression is able to elevate glycogenesis in primary hepatocytes. The glycogen-binding domain is indispensable for the physiological activities of PPP1R3G on glucose metabolism and triglyceride accumulation in the liver. Cumulatively, these data indicate that PPP1R3G plays a critical role in postprandial glucose homeostasis and liver triglyceride metabolism via its regulation on hepatic glycogenesis.

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Hepatic Deletion of Smad7 in Mouse Leads to Spontaneous Liver Dysfunction and Aggravates Alcoholic Liver Injury

Cited by 29 publications

References 38 publications

Inhibitory role of Smad7 in hepatocarcinogenesis in mice and in vitro

Inhibitory role of Smad7 in hepatocarcinogenesis in mice and in vitro

Role of Smads in TGFβ signaling

Regulation of Glucose Homeostasis and Lipid Metabolism by PPP1R3G-mediated Hepatic Glycogenesis

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