p63 regulates an adhesion programme and cell survival in epithelial cells

Carroll, Danielle; Carroll, Jason S.; Leong, Chee‐Onn; Cheng, Fang; Brown, Myles; Mills, Alea A.; Brugge, Joan S.; Ellisen, Leif W.

doi:10.1038/ncb1420

Cited by 381 publications

(460 citation statements)

References 40 publications

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“…MFG-E8 might affect these events during carcinoma tissue growth and/or wound healing, since no substantial defect appeared in the corresponding tissues of MFGE8-deficient mice. As reported recently, p63 induces membrane-anchored molecules including the integrin a 3 and b 4 subunits, envoplakin, Perp and bullous pemphigoid antigen-1/2 (Kurata et al, 2004;Ihrie et al, 2005;Osada et al, 2005a, b;Carroll et al, 2006) for cell-cell and cell-matrix binding. Soluble protein MFG-E8 may provide a novel mechanism of epithelialnonepithelial cell interactions around the p63-expressing cells.…”

Section: Mfge8mentioning

confidence: 67%

p63(TP63) elicits strong trans-activation of the MFG-E8/lactadherin/BA46 gene through interactions between the TA and ΔN isoforms

et al. 2007

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We report here that human MFGE8 encoding milk fat globule-EGF factor 8 protein (MFG-E8), also termed 46 kDa breast epithelial antigen and lactadherin, is transcriptionally activated by p63, or TP63, a p53 (TP53) family protein frequently overexpressed in head-and-neck squamous cell carcinomas, mammary carcinomas and so on. Despite that human MFG-E8 was originally identified as a breast cancer marker, and has recently been reported to provide peptides for cancer immunotherapy, its transcriptional control remains an open question. Observations in immunohistochemical analyses, a tetracycline-induced p63 expression system and keratinocyte cultures suggested a physiological link between p63 and MFGE8. By reporter assays with immediately upstream regions of MFGE8, we determined that the trans-activator (TA) isoforms of p63 activate MFGE8 transcription though a p53/p63 motif at À370, which was confirmed by a chromatin immunoprecipitation experiment. Upon siRNAmediated p63 silencing in a squamous cell carinoma line, MFG-E8 production decreased to diminish Saos-2 cell adhesion. Interestingly, the DN-p63 isoform lacking the TA domain enhanced the MFGE8-activating function of TA-p63, if DN-p63 was dominant over TA-p63 as typically observed in undifferentiated keratinocytes and squamous cell carcinomas, implying a self-regulatory mechanism of p63 by the TA:DN association. MFG-E8 may provide a novel pathway of epithelial-nonepithelial cell interactions inducible by p63, probably in pathological processes.

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Section: Mfge8mentioning

confidence: 67%

p63(TP63) elicits strong trans-activation of the MFG-E8/lactadherin/BA46 gene through interactions between the TA and ΔN isoforms

et al. 2007

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“…Indeed, beyond its dominantnegative effect on p53 suppressor function, DNp63 was found to favour angiogenesis and chemoresistance (Senoo et al, 2002;Wu et al, 2005;Rocco et al, 2006) and to regulate cell-adhesion processes (Carroll et al, 2006;Yang et al, 2006). Conversely, several studies reported a loss of p63 expression in metastatic stages (Barbieri et al, 2006;Adorno et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

TP63 P2 promoter functional analysis identifies β-catenin as a key regulator of ΔNp63 expression

et al. 2011

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The DNp63 protein, a product of the TP63 gene that lacks the N-terminal domain, has a critical role in the maintenance of self renewal and progenitor capacity in several types of epithelial tissues. DNp63 is frequently overexpressed in squamous cell carcinoma (SCC) and in some other epithelial tumours. This overexpression may contribute to tumour progression through dominantnegative effects on the transcriptionally active (TA) isoforms of the p53 family (TAp63, TAp73 and p53), as well as through independent mechanisms. However, the molecular basis of DNp63 overexpression is not fully understood. Here, we show that the expression of DNp63 is regulated by the Wnt/b-catenin pathway in human hepatocellular carcinoma (HCC) and SCC cell lines. This regulation operates in particular through TCF/LEF sites present in the P2 promoter of TP63. In addition, we show that DNp63 and b-catenin are frequently coexpressed and accumulated in oesophageal SCC, but not in HCC. These results suggest that activation of the b-catenin pathway may contribute to overexpression of DNp63 during tumour progression, in a cell type-specific manner.

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“…In stratified epithelia, cells sorted on the basis of high levels of either β1 or α6 integrins appear to have superior clonogenic ability (see below). The transcription factor p63, which transactivates Perp, a protein involved in the assembly of desmosomes, is another factor maintaining the integrity of stratified epithelia [36,37]; Perp-deficient mice suffer severe blistering. p63 has two major isoforms (termed TA and N) that drive at least three transcripts encoding transactivating (TA) and nominally transactivating ( N) isoforms, producing up to six splice variants [38], and it is the TAp63 isoforms that appear to be involved in maintaining cells in an immature state.…”

Section: Self-renewal and The Stem Cell Nichementioning

confidence: 99%

Attributes of adult stem cells

Alison

Islam

2008

The Journal of Pathology

153

115

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While cultured embryonic stem (ES) cells can be harvested in abundance and appear to be the most versatile of cells for regenerative medicine, adult stem cells also hold promise, but the identity and subsequent isolation of these comparatively rare cells remains problematic in most tissues, perhaps with the notable exception of the bone marrow. The ability to continuously self-renew and produce the differentiated progeny of the tissue of their location are their defining properties. Identifying surface molecules (markers) that would aid in stem cell isolation is a major goal. Considerable overlap exists between different putative organspecific stem cells in their repertoire of gene expression, often related to self-renewal, cell survival and cell adhesion. More robust tests of 'stemness' are now being employed, using lineage-specific genetic marking and tracking to show production of long-lived clones and multipotentiality in vivo. Moreover, the characterization of normal stem cells in specific tissues may provide a dividend for the treatment of cancer. The successful treatment of neoplastic disease may well require the specific targeting of neoplastic stem cells, cells that may well have many of the characteristics of their normal counterparts.

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p63 regulates an adhesion programme and cell survival in epithelial cells

Cited by 381 publications

References 40 publications

p63(TP63) elicits strong trans-activation of the MFG-E8/lactadherin/BA46 gene through interactions between the TA and ΔN isoforms

p63(TP63) elicits strong trans-activation of the MFG-E8/lactadherin/BA46 gene through interactions between the TA and ΔN isoforms

TP63 P2 promoter functional analysis identifies β-catenin as a key regulator of ΔNp63 expression

Attributes of adult stem cells

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