NDLI: SMAD Proteins Transactivate the Human ApoCIII Promoter by Interacting Physically and Functionally with Hepatocyte Nuclear Factor 4

Content Provider	Journal of Biological Chemistry (JBC)
Author	Kardassis, Dimitris Pardali, Katerina Zannis, Vassilis I.
Abstract	Cotransfection of HepG2 cells with SMADs established that SMAD3 and SMAD3-SMAD4 transactivated (15–70-fold) the −890/+24 apoCIII promoter and shorter promoter segments, whereas cotransfection with a dominant negative SMAD4 mutant repressed the apoCIII promoter activity by 50%, suggesting that SMAD proteins participate in apoCIII gene regulation. Transactivation required the presence of a hormone response element, despite the fact that SMADs could not bind directly to it. Cotransfection of SMAD3-SMAD4 along with hepatocyte nuclear factor-4 resulted in a strong synergistic transactivation of the −890/+24 apoCIII promoter, proximal promoter segments, or synthetic promoters containing either the apoCIII enhancer or the proximal apoCIII hormone response element. Inhibition of endogenous hepatocyte nuclear factor-4 synthesis by an antisense ribozyme construct reduced the constitutive activity of the apoCIII promoter in HepG2 cells to 10% and abolished the SMAD-mediated transactivation. Co-immunoprecipitation and GST pull-down assays provided evidence for physical interactions between SMAD3, SMAD4, and hepatic nuclear factor-4. Our findings indicate that transforming growth factor β and its signal transducer SMAD proteins can modulate gene transcription by novel mechanisms that involve their physical and functional interaction with hepatocyte nuclear factor-4, suggesting that SMAD proteins may play an important role in apolipoprotein gene expression and lipoprotein metabolism.
Related Links	http://www.jbc.org/content/275/52/41405.abstract
Ending Page	41414
Starting Page	41405
Page Count	10
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	52
Volume Number	275
DOI	10.1074/jbc.M007896200
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2000-12-29
Access Restriction	Open
Subject Keyword	Apolipoprotein (apo) Apolipoprotein AI regulatory protein 1 (ARP-1) Chloramphenicol acetyltransferase (CAT) CCAAT/enhancer box-binding protein (C/EBP) Cytomegalovirus (CMV) VErb-A-related protein (EAR) GlutathioneS-transferase (GST) Hepatocyte nuclear factor (HNF) Hormone response element (HRE) Mad homology domain 1 and 2, respectively (MH1 and -2) Phosphate-buffered saline (PBS) Retinoic acid receptor α (RARα) 9-cis-retinoic acid receptor α (RXRα) Polyacrylamide gel electrophoresis (PAGE) Thyroid hormone receptor β (T3Rβ) Transforming growth factor-β (TGF-β) Polymerase chain reaction (PCR) Reverse transcriptase (RT) MECHANISMS OF SIGNAL TRANSDUCTION
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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