title: 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.
abstract: Our previous studies have shown the induction and maturation of transforming growth factor-beta 1 (TGF-β1) in HCV-infected human hepatoma cells. In this study, we have investigated the molecular mechanism of TGF-β1 gene expression in response to HCV infection. We demonstrate that HCV-induced transcription factors AP-1, Sp1, NF-κB and STAT-3 are involved in TGF-β1 gene expression. Using chromatin immunoprecipitation (ChIP) assay, we further show that AP-1 and Sp1 interact with TGF-b1 promoter in vivo in HCV-infected cells. In addition, we demonstrate that HCV-induced TGF-β1 gene expression is mediated by the activation of cellular kinases such as p38 MAPK, Src, JNK, and MEK1/2. Next, we determined the role of secreted bioactive TGF-β1 in human hepatic stellate cells (HSCs) activation and invasion. Using siRNA approach, we show that HCV-induced bioactive TGF-β1 is critical for the induction of alpha smooth muscle actin (α-SMA) and type 1 collagen, the markers of HSCs activation and proliferation. We further demonstrate the potential role of HCV-induced bioactive TGF-β1 in HSCs invasion/cell migration using a transwell Boyden chamber. Our results also suggest the role of HCV-induced TGF-β1 in HCV replication and release. Collectively, these observations provide insight into the mechanism of TGF-β1 promoter activation, as well as HSCs activation and invasion, which likely manifests in liver fibrosis associated with HCV infection.
authors: Department of Microbiology and Immunology, H.M. Bligh Cancer Research Laboratories, Rosalind Franklin University of Medicine and Science, Chicago Medical School, Chicago, Illinois, USA.
authors: Lance D
authors: LD
authors: Presser
authors: Steven
authors: S
authors: McRae
authors: Gulam
authors: G
authors: Waris
mesh_terms: D000818:Animals; D001483:Base Sequence; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D045683:Furin / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D016174:Hepacivirus / Q000502:physiology*; D055166:Hepatic Stellate Cells / Q000378:metabolism / Q000473:pathology* / Q000821:virology*; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008907:Mink; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D015533:Transcriptional Activation / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000235:genetics* / Q000378:metabolism; D014779:Virus Replication
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C481348:SPZ1 protein, human; D016329:Sp1 Transcription Factor; D018808:Transcription Factor AP-1; D053773:Transforming Growth Factor beta1; D008156:Luciferases; D045683:Furin