p63 regulates an adhesion programme and cell survival in epithelial cells

Department of Cell Biology, Harvard Medical School, 240 Longwood Ave, Boston, MA 02115, USA.
Nature Cell Biology (Impact Factor: 19.68). 05/2006; 8(6):551-561. DOI: 10.1038/ncb1420
Source: PubMed


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 TAp63 or Np63 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 4 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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Available from: Chee-Onn Leong, Jun 23, 2014
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    • "Downregulation of ΔNp63 in Lbh-deficient MaSCs could be responsible for a range of phenotypes observed in our model. ΔNp63 controls stem cell self-renewal and quiescence, and promotes basal epithelial characteristics by regulating transcription of genes involved in cell proliferation, adhesion and the basal cytoskeleton, including K5 (Carroll et al., 2006; Romano et al., 2009; Wu et al., 2003; Yalcin-Ozuysal et al., 2010), which we found to be induced by LBH in HC11. By modulating LBH and p63 expression in established MEC culture systems, we demonstrate that LBH induces ΔNp63 at the mRNA level and that ΔNp63, indeed, acts downstream of LBH in promoting stemness and basal K5 expression. "
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    ABSTRACT: The identification of multipotent mammary stem cells (MaSCs) has provided an explanation for the unique regenerative capacity of the mammary gland throughout adult life. However, it remains unclear what genes maintain MaSCs and control their specification into the two epithelial lineages: luminal and basal. LBH is a novel transcription co-factor in the WNT pathway with hitherto unknown physiological function. LBH is expressed during mammary gland development and aberrantly overexpressed in aggressive 'basal' subtype breast cancers. Here, we have explored the in vivo role of LBH in mammopoiesis. We show that in postnatal mammary epithelia, LBH is predominantly expressed in the Lin(-)CD29(high)CD24(+) basal MaSC population. Upon conditional inactivation of LBH, mice exhibit pronounced delays in mammary tissue expansion during puberty and pregnancy, accompanied by increased luminal differentiation at the expense of basal lineage specification. These defects could be traced to a severe reduction in the frequency and self-renewal/differentiation potential of basal MaSCs. Mechanistically, LBH induces expression of key epithelial stem cell transcription factor ΔNp63 to promote a basal MaSC state and repress luminal differentiation genes, mainly that encoding estrogen receptor α (Esr1/ERα). Collectively, these studies identify LBH as an essential regulator of basal MaSC expansion/maintenance, raising important implications for its potential role in breast cancer pathogenesis. © 2015. Published by The Company of Biologists Ltd.
    Development 02/2015; 142(5). DOI:10.1242/dev.110403 · 6.46 Impact Factor
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    • "Published microarray data from human non-transformed MCF10A breast epithelial cells (Carroll et al., 2006) were re-analyzed for possible regulation of apoptosis-related genes by ∆Np63. shRNA against the p63 DNA-binding domain (DBD) was used to knock down all p63 isoforms (top), whereas shRNA against the p63 TA domain was TAp63-specific (bottom). "
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    ABSTRACT: In embryogenesis, p63 is essential to develop mammary glands. In the adult mammary gland, p63 is highly expressed in the basal cell layer that comprises myoepithelial and interspersed stem/progenitor cells, and has limited expression in luminal epithelial cells. In adult skin, p63 has a crucial role in the maintenance of epithelial stem cells. However, it is unclear whether p63 also has an equivalent role as a stem/progenitor cell factor in adult mammary epithelium. We show that p63 is essential in vivo for the survival and maintenance of parity-identified mammary epithelial cells (PI-MECs), a pregnancy-induced heterogeneous population that survives post-lactational involution and contain multipotent progenitors that give rise to alveoli and ducts in subsequent pregnancies. p63+/- glands are normal in virgin, pregnant and lactating states. Importantly, however, during the apoptotic phase of post-lactational involution p63+/- glands show a threefold increase in epithelial cell death, concomitant with increased activation of the oncostatin M/Stat3 and p53 pro-apoptotic pathways, which are responsible for this phase. Thus, p63 is a physiologic antagonist of these pathways specifically in this regressive stage. After the restructuring phase when involution is complete, mammary glands of p63+/- mice again exhibit normal epithelial architecture by conventional histology. However, using Rosa(LSL-LacZ);WAP-Cre transgenics (LSL-LacZ, lox-stop-lox β-galactosidase), a genetic in vivo labeling system for PI-MECs, we find that p63+/- glands have a 30% reduction in the number of PI-MEC progenitors and their derivatives. Importantly, PI-MECs are also cellular targets of pregnancy-promoted ErbB2 tumorigenesis. Consistent with their PI-MEC pool reduction, one-time pregnant p63+/- ErbB2 mice are partially protected from breast tumorigenesis, exhibiting extended tumor-free and overall survival, and reduced tumor multiplicity compared with their p63+/+ ErbB2 littermates. Conversely, in virgin ErbB2 mice p63 heterozygosity provides no survival advantage. In sum, our data establish that p63 is an important survival factor for pregnancy-identified PI-MEC progenitors in breast tissue in vivo.Cell Death and Differentiation advance online publication, 17 January 2014; doi:10.1038/cdd.2013.199.
    Cell death and differentiation 01/2014; 21(4). DOI:10.1038/cdd.2013.199 · 8.18 Impact Factor
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    • "Cell Lines MCF10A, 293T, and HC11 cells were maintained as previously described (Carroll et al., 2006; Taverna et al., 1991). Cell line HC11 (Taverna et al., 1991) was a generous gift of Joseph Jerry (Pioneer Valley Life Sciences Institute, Springfield). "
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    ABSTRACT: The mammary epithelium is organized as a bilayer of luminal and basal/myoepithelial cells. During pregnancy, the luminal compartment expands for milk production, while basal cells are thought to provide structural and contractile support. Here, we reveal a pregnancy-specific role of basal epithelia as a central coordinator of lactogenesis. We demonstrate that genetic deletion of the transcription factor p63 (Trp63) gene exclusively within basal cells of the adult gland during pregnancy leads to dramatic defects in luminal cell proliferation and differentiation, resulting in lactation failure. This phenotype is explained by direct transcriptional activation of the epidermal growth factor family ligand gene Nrg1 by p63 selectively in basal cells, which is required for luminal ERBB4/STAT5A activation and consequent luminal progenitor cell maturation. Thus, paracrine basal-to-luminal cell signaling, controlled by p63 via NRG1, orchestrates the entire lactation program. Collectively, these findings redefine the paradigm for cellular interactions specifying the functional maturation of the mammary gland.
    Developmental Cell 01/2014; 28(2). DOI:10.1016/j.devcel.2013.11.019 · 9.71 Impact Factor
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