p63 regulates an adhesion programme and cell survival in epithelial cells

Abstract

p63 is critical for epithelial development yet little is known about the transcriptional programmes it regulates. By characterising transcriptional changes and cellular effects following modulation of p63 expression, we have defined a vital role for p63 in cellular adhesion. Knockdown of p63 expression caused downregulation of cell adhesion-associated genes, cell detachment and anoikis in mammary epithelial cells and keratinocytes. Conversely, overexpression of the TAp63γ or ΔNp63α isoforms of p63 upregulated cell adhesion molecules, increased cellular adhesion and conferred resistance to anoikis. Apoptosis induced by loss of p63 was rescued by signalling downstream of β4 integrin. Our results implicate p63 as a key regulator of cellular adhesion and survival in basal cells of the mammary gland and other stratified epithelial tissues.

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Figure 1: Loss of endogenous p63 expression induces detachment and death in mammary epithelial cells.
Figure 2: Identification of an adhesion subprogramme regulated by p63.
Figure 3: Regulation of cellular adhesion factors by p63.
Figure 4: p63 activates adhesion–integrin signalling and promotes cell adhesion.
Figure 5: Elevated p63 expression suppresses apoptosis following cell detachment.
Figure 6: β4 integrin partially protects from anoikis induced by p63 loss.
Figure 7: p63 controls a cellular adhesion programme in primary mammary epithelial cells.
Figure 8: p63 regulates cellular adhesion and survival in other epithelial tissues.

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Acknowledgements

The authors would like to thank F. McKeon for p63 cDNAs and comments on the manuscript, M. Reginato (Drexel University College of Medicine) for helpful discussions and critical reading of the manuscript, P. Grosu and the Bauer Center for Genomics Research, Harvard University, for assistance with computational software. This work was supported by the Association for International Cancer Research (AICR) #04-156 (D.L.), the Deparment of Defense (DOD) Breast Cancer Research Program Awards DAMD17-01-1-0222 (M.B.) w81XWH-04-1-0512 (J.C.), National Institute of Dental and Craniofacial Research (NIDCR) DE15945-01, The Avon Foundation, and the Mary Kay Ash Charitable Foundation (L.E.), NCI CA080111, Breast Cancer Research Foundation, and DOD DAMD17-02-1-0692 (J.S.B.), National Institutes of Health (NIH) AR47898 (A.M.).

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Correspondence to Joan S. Brugge.

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