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P63 regulates tubular formation via epithelial-to-mesenchymal transition

Oncogene volume 33, pages 1548–1557 (2014)Cite this article

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Abstract

P63, a p53 family member, is expressed as TA and ΔN isoforms. Interestingly, both TAp63 and ΔNp63 are transcription factors, and regulate both common and distinct sets of target genes. p63 is required for survival of some epithelial cell lineages, and lack of p63 leads to loss of epidermis and other epithelia in humans and mice. Here, we explored the role of p63 isoforms in cell proliferation, migration and tubulogenesis by using Madin–Darby Canine Kidney (MDCK) tubular epithelial cells in two- or three-dimensional (2-D or 3-D) culture. We found that like downregulation of p53, downregulation of p63 and TAp63 decreases expression of growth-suppressing genes, including p21, PUMA and MIC-1, and consequently promotes cell proliferation and migration in 2-D culture. However, in 3-D culture, downregulation of p63, especially TAp63, but not p53, decapacitates MDCK cells to form a cyst structure through enhanced epithelial-to-mesenchymal transition (EMT). In contrast, downregulation of ΔNp63 inhibits MDCK cell proliferation and migration in 2-D culture, and delays but does not block MDCK cell cyst formation and tubulogenesis in 3-D culture. Consistent with this, downregulation of ΔNp63 markedly upregulates growth-suppressing genes, including p21, PUMA and MIC-1. Taken together, these data suggest that TAp63 is the major isoform required for tubulogenesis by maintaining an appropriate level of EMT, whereas ΔNp63 fine-tunes the rate of cyst formation and tubulogenesis by maintaining an appropriate expression level of genes involved in cell cycle arrest and apoptosis.

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Acknowledgements

This work was supported in part by the National Institutes of Health grants CA102188, CA108122 and CA076069. We thank Jin Zhang for helpful comments on this manuscript.

Author Contributions

Y Zhang and W Yan did the experiments and analyzed the data; X Chen supervised the project and analyzed the data; and Y Zhang, W Yan and X Chen wrote the paper. All authors read and commented on the draft versions of the manuscript and approved the final version.

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  1. Y Zhang and W Yan: These authors contributed equally to this work.

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  1. Center for Comparative Oncology, Schools of Medicine and Veterinary Medicine, University of California at Davis, Davis, CA, USA

    Y Zhang, W Yan & X Chen

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Correspondence to X Chen.

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Zhang, Y., Yan, W. & Chen, X. P63 regulates tubular formation via epithelial-to-mesenchymal transition. Oncogene 33, 1548–1557 (2014). https://doi.org/10.1038/onc.2013.101

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