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    Transforming growth factor-beta 1 responsiveness of the rat osteocalcin gene is mediated by an activator protein-1 binding site

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    Authors
    Banerjee, Chaitali
    Stein, Janet L.
    Van Wijnen, Andre J.
    Frenkel, Baruch
    Lian, Jane B.
    Stein, Gary S.
    UMass Chan Affiliations
    Department of Cell Biology
    Graduate School of Biomedical Sciences
    Document Type
    Journal Article
    Publication Date
    1996-05-01
    Keywords
    Animals; Base Sequence; Binding Sites; DNA-Binding Proteins; Fos-Related Antigen-2; *Gene Expression Regulation; Methylation; Molecular Sequence Data; Mutagenesis; Osteocalcin; Osteosarcoma; Phosphorylation; Promoter Regions (Genetics); Rats; Transcription Factor AP-1; Transcription Factors; Transfection; Transforming Growth Factor beta; Tumor Cells, Cultured
    Life Sciences
    Medicine and Health Sciences
    
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    Link to Full Text
    https://doi.org/10.1210/en.137.5.1991
    Abstract
    Osteocalcin (OC), a bone specific protein expressed during differentiation and mineralization of the bone extracellular matrix, is down-regulated upon treatment with transforming growth factor (TGF)-beta 1. To address the potential role of OC gene expression in relation to TGF-beta 1 regulation of bone formation and resorption, we examined the transcriptional activity of the rat OC promoter after TGF-beta 1 treatment. 5' deletion analysis of rat OC promoter-chloramphenicol acetyltransferase constructs demonstrated that TGF-beta 1 treatment repressed chloramphenicol acetyltransferase activity by 2.4-fold in transient transfections of ROS 17/2.8 cells. A 29-bp region between -162 and -134 identified as the TGF-beta 1 response domain, conferred TGF-beta 1 responsiveness to the -108 to +24 rat OC basal promoter in an orientation dependent manner. Mutation of an activator protein-1/cAMP-response element-like motif (- 146 to -139) abolished TGF-beta 1 responsiveness of the construct. In vitro gel-mobility shift and competition assays using wild-type and mutated oligonucleotides and antibodies indicate that Fra-2, a Fos related transcription factor, binds to this motif. We show that Fra-2 is an activator of the OC promoter, and TGF-beta 1 inhibits this activation. Our results demonstrate that Fra-2 is hyperphosphorylated upon TGF-beta 1 treatment of ROS 17/2.8 cells. Additionally, treatment of cells with a staurosporine protein kinase C inhibitor abrogates TGF-beta 1 mediated down-regulation of the OC promoter activity. Together, these results demonstrate that TGF-beta 1 responsiveness of the rat osteocalcin gene in ROS 17/2.8 cells is mediated through an activator protein-1 like cis-acting element that interacts with Fra-2. Furthermore, our results are consistent with a critical role for TGF-beta 1 induced phosphorylation of Fra-2 in the repression of OC gene transcription.
    Source

    Endocrinology. 1996 May;137(5):1991-2000.

    DOI
    10.1210/en.137.5.1991
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/34086
    PubMed ID
    8612540
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    Link to article in PubMed

    ae974a485f413a2113503eed53cd6c53
    10.1210/en.137.5.1991
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