Activation of TGF-β1 Promoter by Hepatitis C Virus-Induced AP-1 and Sp1: Role of TGF-β1 in Hepatic Stellate Cell Activation and Invasion

Presser, Lance; McRae, Steven; Waris, Gulam

doi:10.1371/journal.pone.0056367

Cited by 70 publications

(76 citation statements)

References 70 publications

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“…It has been well accepted that cellular kinases play critical roles in HCV-mediated pathogenesis by activating downstream transcription factors. We and others have shown the activation of various cellular kinases such as JNK, p38 MAPK, ERK, Src, PI3K, and JAK in response to HCV infection, and these kinases induce transcription factors Nrf2, NF-B, AP-1, Sp1, HIF-1␣, ATF6, and STAT-3 (22)(23)(24)(25)(26).…”

Section: Hepatitis C Virus (Hcv)mentioning

confidence: 95%

Mechanism of Hepatitis C Virus (HCV)-induced Osteopontin and Its Role in Epithelial to Mesenchymal Transition of Hepatocytes

Iqbal

McRae

Banaudha

et al. 2013

Journal of Biological Chemistry

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Background:The mechanism underlying HCV-induced OPN remains elusive. Results: HCV-induced Ca 2ϩ signaling, oxidative stress, and activation of AP-1 and Sp1 play a critical role in OPN activation. Conclusion: OPN plays important roles in EMT and cell migration induced by HCV through the activation of Akt, GSK-3␤, and ␤-catenin. Significance: Our findings provide a novel implication of OPN in HCV-induced HCC.

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Section: Hepatitis C Virus (Hcv)mentioning

confidence: 95%

Mechanism of Hepatitis C Virus (HCV)-induced Osteopontin and Its Role in Epithelial to Mesenchymal Transition of Hepatocytes

Iqbal

McRae

Banaudha

et al. 2013

Journal of Biological Chemistry

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“…Herein, the loss-and gain-of-function studies showed that p-CREB-1 upregulated TGF-β1 expression and was required for TGF-β1 auto-induction in HSCs. Previous studies demonstrated that TGF-β1 expression may be regulated by several transcription factors such as AP-1, SP-1, nuclear factor (NF)-κB, Kruppel-like factor 4 (gut) (KLF4) and signal transducer and activator of transcription 3 (STAT3) in various experimental model systems including liver fibrosis (24)(25)(26)(27). In the present study, we reported that another transcription factor, p-CREB-1, was capable of transactivating TGF-β1 expression.…”

Section: Discussionmentioning

confidence: 99%

p-CREB-1 promotes hepatic fibrosis through the transactivation of transforming growth factor-β1 expression in rats

Wang

Deng

Zhuang

et al. 2016

International Journal of Molecular Medicine

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Abstract. Phosphorylated cAMP-responsive element binding protein-1 (p-CREB-1) is an important transcription factor which has been reported to be implicated in fibrogenesis. However, the association between p-CREB-1 and transforming growth factor-β1 (TGF-β1)-mediated liver fibrogenesis remains poorly understood. In the present study, exogenous TGF-β1 recombinant protein was used to activate hepatic stellate cells (HSCs), and we established a rat model of tetrachloromethane (CCl 4 )-induced liver fibrosis. Loss-and gain-of-function studies were performed to examine the role of p-CREB-1 in liver fibrogenesis, and the detailed mechanism responsible for these effects was further explored using chromatin immunoprecipitation and luciferase reporter gene assays. We found that p-CREB-1 expression was significantly upregulated in a rat model of hepatic fibrosis. We also demonstrated that p-CREB-1 increased TGF-β1 expression and auto-induction in HSCs, through directly binding to the CRE site within the TGF-β1 promoter in order to enhance its transcriptional activity. Moreover, lentivirus-mediated CREB-1 overexpression promoted hepatic fibrogenesis in rats. These findings suggest that p-CREB-1 may function as a potent profibrogenic factor through the transactivation of TGF-β1 expression in liver fibrosis. IntroductionHepatic fibrosis, characterized by the excessive production and deposition of the extracellular matrix (ECM), is a common pathologic change observed in the progression of various chronic liver diseases to cirrhosis (1-3). Transforming growth factor-β1 (TGF-β1), the most potent profibrogenic cytokine currently known, stimulates the activation and transformation of hepatic stellate cells (HSCs) into myofibroblasts producing abnormal and abundant ECM (4,5). It has been reported that TGF-β1 binds to TGF-β type II receptors on the cell surface, and then recruits type I receptors; as a consequence, the type II receptor kinase phosphorylates the type I receptors and intracellular signal molecules such as Smads. Phosphorylated (p-)Smad2 and/or p-Smad3 form heteroligomers with Smad4, which translocate into the nucleus to control the ECM gene transcription (6-7). On the contrary, blocking TGF-β1 signaling may inhibit collagen production and promote the degradation of collagen (8,9). The roles of TGF-β1 in HSCs activation and liver fibrosis have been intensively studied; however, the transcriptional regulation of TGF-β1 remains poorly understood.Cyclic adenosine 3' ,5'-monophosphate (cAMP)-responsive element (CRE) binding protein-1 (CREB-1), a eukaryotic transcription factor, binds to CRE sites in the promoters of various cytokines to widely regulate gene transcription (10,11). The role of CREB-1 in fibrogenesis remains controversial. Several studies have reported that CREB-1 exerts anti-fibrotic effects, such as in myocardial fibrosis and pulmonary fibrosis (12,13). On the contrary, CREB-1 facilitated high glucose induced renal tubulointerstitial fibrosis in diabetic nephropathy (14). Currently, there limited research r...

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“…These results suggest a potential link between the LPA/LPA 2 signaling axis (involving the ERK1/2, p38 MAPK, and Akt pathways) and TGF-b secretion in human lung fibroblasts. In fact, earlier studies have shown the involvement of phosphatidylinositol 3-kinase and MAPK pathways in the production of TGF-b by macrophages (38) and the hepatitis C virus-mediated activation of TGF-b1 gene by Src and MAPKs in a human hepatoma cell line (39). LPA levels are elevated in the BAL fluid of patients with IPF and in animal models of pulmonary fibrosis (16), which may provide an important mediator in initiating TGF-b secretion from fibroblasts and other cell types in the lung.…”

Section: Discussionmentioning

confidence: 99%

Lysophosphatidic Acid Receptor–2 Deficiency Confers Protection against Bleomycin-Induced Lung Injury and Fibrosis in Mice

Huang¹,

Patel

et al. 2013

Am J Respir Cell Mol Biol

102

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Idiopathic pulmonary fibrosis is a devastating disease characterized by alveolar epithelial cell injury, the accumulation of fibroblasts/ myofibroblasts, and the deposition of extracellular matrix proteins. Lysophosphatidic acid (LPA) signaling through its G proteincoupled receptors is critical for its various biological functions. Recently, LPA and LPA receptor 1 were implicated in lung fibrogenesis. However, the role of other LPA receptors in fibrosis remains unclear. Here, we use a bleomycin-induced pulmonary fibrosis model to investigate the roles of LPA 2 in pulmonary fibrogenesis. In the present study, we found that LPA 2 knockout (Lpar2 2/2 ) mice were protected against bleomycin-induced lung injury, fibrosis, and mortality, compared with wild-type control mice. Furthermore, LPA 2 deficiency attenuated the bleomycin-induced expression of fibronectin (FN), a-smooth muscle actin (a-SMA), and collagen in lung tissue, as well as levels of IL-6, transforming growth factor-b (TGF-b), and total protein in bronchoalveolar lavage fluid. In human lung fibroblasts, the knockdown of LPA 2 attenuated the LPA-induced expression of TGF-b1 and the differentiation of lung fibroblasts to myofibroblasts, resulting in the decreased expression of FN, a-SMA, and collagen, as well as decreased activation of extracellular regulated kinase 1/2, Akt, Smad3, and p38 mitogen-activated protein kinase. Moreover, the knockdown of LPA 2 with small interfering RNA also mitigated the TGF-b1-induced differentiation of lung fibroblasts. In addition, LPA 2 deficiency significantly attenuated the bleomycin-induced apoptosis of alveolar and bronchial epithelial cells in the mouse lung. Together, our data indicate that the knockdown of LPA 2 attenuated bleomycin-induced lung injury and pulmonary fibrosis, and this may be related to an inhibition of the LPA-induced expression of TGF-b and the activation and differentiation of fibroblasts.

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Activation of TGF-β1 Promoter by Hepatitis C Virus-Induced AP-1 and Sp1: Role of TGF-β1 in Hepatic Stellate Cell Activation and Invasion

Cited by 70 publications

References 70 publications

Mechanism of Hepatitis C Virus (HCV)-induced Osteopontin and Its Role in Epithelial to Mesenchymal Transition of Hepatocytes

Mechanism of Hepatitis C Virus (HCV)-induced Osteopontin and Its Role in Epithelial to Mesenchymal Transition of Hepatocytes

p-CREB-1 promotes hepatic fibrosis through the transactivation of transforming growth factor-β1 expression in rats

Lysophosphatidic Acid Receptor–2 Deficiency Confers Protection against Bleomycin-Induced Lung Injury and Fibrosis in Mice

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