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The transcription factor snail represses Crumbs3 expression and disrupts apico-basal polarity complexes

Oncogene volume 27, pages 3875–3879 (2008)Cite this article

Abstract

In epithelial cells, the tight junction divides the plasma membrane into distinct apical and basolateral domains. Polarization is essential for epithelial cell function, and apico-basal cell polarity is lost during the epithelial to mesenchymal transition (EMT), a program of events characterized not only by loss of cell polarity, but also by enhanced cell motility and increased cell invasion. Among several apically localized protein complexes, the Crumbs and Par protein complexes have pivotal roles in control of epithelial polarity and apical membrane formation. Here, we demonstrate that the Snail transcriptional repressor antagonizes expression of the Crumbs polarity complex. We show that Snail abolishes localization of the Crumbs and Par complexes to the tight junction, decreases Crumbs complex protein levels and suppresses Crumbs3 transcription. Evidence that Snail acts directly to antagonize Crumbs3 promoter activity is presented. Strikingly, we note that reexpression of exogenous Crumbs3 in Snail-expressing Madin–Darby Canine Kidney cells partially restores cell–cell junctions. Moreover, we find that the EMT inducer transforming growth factor-β elicits transcriptional repression of Crumbs3 and results in a measurable loss of Crumbs3 protein. Our findings provide new insights into the links between the transcriptional repression function of Snail and its role in antagonizing key apico-basal polarity factors during EMT.

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Acknowledgements

This work was supported by NIH Grants DK058208 and DK069605 (to BM). ELW was supported by the Cancer Biology Training Program at the University of Michigan and an individual National Research Service Award (NIH Grants 5-T32-CA09676 and 5-F32-GM079906). This work utilized the Morphology and Image Analysis Core of the Michigan Diabetes Research and Training Center funded by NIH Grant 5-P60-DK20572. We thank Ron Koenig, Sanj Patel, Stephen Lentz, Toby Hurd, Shuling Fan, Jennifer Harder, Jay Pieczynski, Qian Wang and Kunyoo Shin for technical advice, reagents and critical discussions concerning this article.

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Authors and Affiliations

  1. Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA

    E L Whiteman, C-J Liu, E R Fearon & B Margolis

  2. Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA

    E R Fearon

  3. Department of Pathology, University of Michigan, Ann Arbor, MI, USA

    E R Fearon

  4. Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA

    E R Fearon & B Margolis

  5. Department of Biological Chemistry, University of Michigan, Ann Arbor, MI, USA

    B Margolis

Authors
  1. E L Whiteman
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  2. C-J Liu
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  3. E R Fearon
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  4. B Margolis
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Correspondence to B Margolis.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Whiteman, E., Liu, CJ., Fearon, E. et al. The transcription factor snail represses Crumbs3 expression and disrupts apico-basal polarity complexes. Oncogene 27, 3875–3879 (2008). https://doi.org/10.1038/onc.2008.9

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