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    SFRP-4 abrogates Wnt-3a-induced ß-catenin and Akt/PKB signalling and reverses a Wnt-3a-imposed inhibition of in vitro mammary differentiation

    Access Status
    Open access via publisher
    Authors
    Constantinou, T.
    Baumann, F.
    Lacher, M.
    Saurer, S.
    Friis, R.
    Dharmarajan, Arunasalam
    Date
    2008
    Type
    Journal Article
    
    Metadata
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    Citation
    Constantinou, T. and Baumann, F. and Lacher, M. and Saurer, S. and Friis, R. and Dharmarajan, A. 2008. SFRP-4 abrogates Wnt-3a-induced ß-catenin and Akt/PKB signalling and reverses a Wnt-3a-imposed inhibition of in vitro mammary differentiation. Journal of Molecular Signaling. 3.
    Source Title
    Journal of Molecular Signaling
    DOI
    10.1186/1750-2187-3-10
    School
    School of Biomedical Sciences
    URI
    http://hdl.handle.net/20.500.11937/25446
    Collection
    • Curtin Research Publications
    Abstract

    Background: Conserved Wnt ligands are critical for signalling during development; however, various factors modulate their activity. Among these factors are the Secreted Frizzled-Related Proteins (SFRP). We previously isolated the SFRP-4 gene from an involuting rat mammary gland and later showed that transgenic mice inappropriately expressing SFRP-4 during lactation exhibited a high level of apoptosis with reduced survival of progeny. Results: In order to address the questions related to the mechanism of Wnt signalling and its inhibition by SFRP-4 which we report here, we employed partially-purified Wnt-3a in a co-culture model system. Ectopic expression of SFRP-4 was accomplished by infection with a pBabepuro construct. The co-cultures comprised Line 31E mouse mammary secretory epithelial cells and Line 30F, undifferentiated, fibroblast-like mouse mammary cells. In vitro differentiation of such co-cultures can be demonstrated by induction of the ß-casein gene in response to lactogenic hormones. We show here that treatment of cells with partially-purified Wnt-3a initiates Dvl-3, Akt/PKB and GSK-3ß hyperphosphorylation and ß-catenin activation. Furthermore, while up-regulating the cyclin D1 and connexin-43 genes and elevating transepithelial resistance of Line 31E cell monolayers, Wnt-3a treatment abrogates differentiation of co-cultures in response to the lactogenic hormones prolactin, insulin and glucocorticoid. Cells which express SFRP-4, however, are largely unaffected by Wnt-3a stimulation. Since a physical association between Wnt-3a and SFRP-4 could be demonstrated with immunoprecipitation/Western blotting experiments, this interaction, presumably owing to the Frizzled homology region typical of all SFRPs, explains the refractory response to Wnt-3a which was observed. Conclusion: This study demonstrates that Wnt-3a treatment activates the Wnt signalling pathway and interferes with in vitro differentiation of mammary co-cultures to ß-casein production in response to lactogenic hormones. Similarly, in another measure of differentiation, following Wnt-3a treatment mammary epithelial cells could be shown to up-regulate the cyclin D1 and connexin-43 genes while phenotypically they show increased transepithelial resistance across the cell monolayer. All these behavioural changes can be blocked in mammary epithelial cells expressing SFRP-4. Thus, our data illustrate in an in vitro model a mechanism by which SFRP-4 can modulate a differentiation response to Wnt-3a. © 2008 Constantinou et al; licensee BioMed Central Ltd.

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