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Transcriptional repressor of vasoactive intestinal peptide receptor mediates repression through interactions with TFIIB and TFIIEbeta.

ABSTRACT: The transcriptional repressor for rat vasoactive-intestinal-polypeptide receptor 1 (VIPR-RP) is a recently characterized transcription factor that belongs to a family of proteins, which include components of the DNA replication factor C complex. In this study, I investigated the mechanisms by which VIPR-RP represses transcription. I show here that transcriptional repression by VIPR-RP is mediated by a histone deacetylase-independent mechanism. I provide evidence that VIPR-RP makes direct physical contacts with two proteins of the basal transcription apparatus, the transcription factors TFIIB and TFIIEbeta. The interaction with TFIIB is mediated by the N-terminal 180 amino acids, whereas the interactive domain with TFIIEbeta is located between residues 367 and 527 of VIPR-RP. Using gel mobility-shift assays I demonstrated that interaction between VIPR-RP and TFIIB prevents the recruitment of TFIIB into a DNA-TATA-box-binding protein complex. My results indicate that VIPR-RP mediates transcriptional repression through direct interactions with the general transcription machinery.

SUBMITTER: Pei L

PROVIDER: S-EPMC1222266 | biostudies-other | 2001 Dec

REPOSITORIES: biostudies-other

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Project description:Formation of intrahepatic bile ducts (IHBDs) proceeds in accordance with their microenvironment. Particularly, mesenchymal cells around portal veins regulate the differentiation and ductular morphogenesis of cholangiocytes in the developing liver; however, further studies are needed to fully understand the arrangement of IHBDs into a continuous hierarchical network. This study aims to clarify the interaction between biliary and liver mesenchymal cells during IHBD formation. To identify candidate factors contributing to this cell-cell interaction, mesenchymal cells were isolated from embryonic day 16.5 matrix metalloproteinase 14 (MMP14)-deficient (knockout [KO]) mice livers, in which IHBD formation is retarded, and compared with those of the wild type (WT). WT mesenchymal cells significantly facilitated the formation of luminal structures comprised of hepatoblast-derived cholangiocytes (cholangiocytic cysts), whereas MMP14-KO mesenchymal cells failed to promote cyst formation. Comprehensive analysis revealed that expression of vasoactive intestinal peptide (VIP) was significantly suppressed in MMP14-KO mesenchymal cells. VIP and VIP receptor 1 (VIPR1) were mainly expressed in periportal mesenchymal cells and cholangiocytic progenitors during IHBD development, respectively, in vivo. VIP/VIPR1 signaling significantly encouraged cholangiocytic cyst formation and up-regulated tight junction protein 1, cystic fibrosis transmembrane conductance regulator, and aquaporin 1, in vitro. VIP antagonist significantly suppressed the tight junction assembly and the up-regulation of ion/water transporters during IHBD development in vivo. In a cholestatic injury model of adult mice, exogenous VIP administration promoted the restoration of damaged tight junctions in bile ducts and improved hyperbilirubinemia. Conclusion: VIP is produced by periportal mesenchymal cells during the perinatal stage. It supports bile duct development by establishing tight junctions and up-regulating ion/water transporters in cholangiocytes. VIP contributes to prompt recovery from cholestatic damage through the establishment of tight junctions in the bile ducts.

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Transcriptional repressor of vasoactive intestinal peptide receptor mediates repression through interactions with TFIIB and TFIIEbeta.

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