Transcriptional Network of p63 in Human Keratinocytes

Pozzi, Silvia; Zambelli, Federico; Merico, Daniele; Pavesi, Giulio; Robert, Amélie; Maltère, Peggy; Gidrol, Xavier; Mantovani, Roberto; Viganò, M. Alessandra

doi:10.1371/journal.pone.0005008

Cited by 43 publications

(60 citation statements)

References 56 publications

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“…KLF5, also a putative p63 target (NC and RM, unpublished), is upregulated during this process (Figure 2b). KC differentiation was monitored by measuring mRNA levels of Involucrin and p21, which were reported to increase (Figure 2a, right panels), while DNp63a and two previously identified targets activated by p63, SMAD7 and SMURF2, significantly decreased (Pozzi et al, 2009). We also monitored KLF4 expression by immunofluorescence staining with p63 and KLF4 antibodies.…”

Section: Klf4 Is Regulated During Differentiation Of the Skinmentioning

confidence: 91%

“…p53 is not bound to any of the analyzed regions. The C40 region on the p63 locus served as a positive control for p63 binding (Pozzi et al, 2009). Additional ChIP results are given in Supplementary 1.…”

Section: Klf4 Is a Transcriptional Target Of P63mentioning

confidence: 99%

“…Maintenance, differentiation and transfection of primary human neonatal keratinocytes (hnKCs; CellNtec, CH) were conducted as previously described (Pozzi et al, 2009). For knockdown experiments, 50 nM siRNA oligonucleotides, with a scrambled sequence (Ambion, Foster City, CA, USA), or targeting the central DNA-binding domain of p63 or against p53 (5 0 -GACUCCAGUGGUAAUCUACTT-3 0 ), were used.…”

Section: Cell Culture and Transfectionsmentioning

confidence: 99%

“…Primer pairs are listed in Supplementary 3. Fold enrichment for each TF was calculated as previously described (Pozzi et al, 2009). …”

Section: Chromatin Immunoprecipitationmentioning

confidence: 99%

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Mutant p53 subverts p63 control over KLF4 expression in keratinocytes

et al. 2010

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Genetic experiments established that p63 is crucial for the development and maintenance of pluri-stratified epithelia and KLF4 for the barrier function of the skin. KLF4 is one of the factors that reprogram differentiated cells to iPS. We investigated the relationship between p63 and KLF4 using RNA interference, overexpression, chromatin immunoprecipitation and transient transfections with reporter constructs. We find that p63 directly represses KLF4 in normal keratinocytes (KCs) by binding to upstream promoter sites. Unlike p63, KLF4 levels are high in the upper layers of human skin and increase upon differentiation of KCs in vitro. In HaCaT KCs, which harbor two mutant alleles of p53, inactivation of p63 and of mutant p53 leads to KLF4 repression. p63 and p53 mutants are bound to sites in the KLF4 core promoter. Importantly, expression of the H179Y and R282Q p53 mutants in primary KCs is sufficient to activate endogenous KLF4. Finally, immunohistochemical analysis of tissue arrays confirms increased coexpression of KLF4 and mutant p53 in squamous cell carcinomas. Our data indicate that suppression of KLF4 is part of the growth-promoting strategy of p63 in the lower layers of normal epidermis, and that tumor-predisposing p53 mutations hijack p63 to a different location on the promoter, turning it into an activator of this reprogramming factor.

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Section: Klf4 Is Regulated During Differentiation Of the Skinmentioning

confidence: 91%

Section: Klf4 Is a Transcriptional Target Of P63mentioning

confidence: 99%

Section: Cell Culture and Transfectionsmentioning

confidence: 99%

“…Primer pairs are listed in Supplementary 3. Fold enrichment for each TF was calculated as previously described (Pozzi et al, 2009). …”

Section: Chromatin Immunoprecipitationmentioning

confidence: 99%

See 2 more Smart Citations

Mutant p53 subverts p63 control over KLF4 expression in keratinocytes

et al. 2010

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“…3,26 Moreover, Chip-seq and Chip-on-chip analysis experiments performed on somatic epithelial cells identified p63-target genes related to cardiac development. 17,58 Finally, a specific activity of a strong p63 enhancer was reported in the embryonic heart area of transgenic mice. 59 As stated above, p63 expression was detected by in situ hybridization in the branchial (pharyngeal) arches, where cardiac progenitors are located and reside close to ectodermal and endodermal progenitor cells before their migration to the cardiac tube.…”

Section: In Tap63mentioning

confidence: 97%

Regulation of skin aging and heart development by TAp63

et al. 2011

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Since the discovery of the TP63 gene in 1998, many studies have demonstrated that DNp63, a p63 isoform of the p53 gene family, is involved in multiple functions during skin development and in adult stem/progenitor cell regulation. In contrast, TAp63 studies have been mostly restricted to its apoptotic function and more recently as the guardian of oocyte integrity. TAp63 endogenous expression is barely detectable in embryos and adult (except in oocytes), presumably because of its rapid degradation and the lack of antibodies able to detect weak expression. Nevertheless, two recent independent studies have demonstrated novel functions for TAp63 that could have potential implications to human pathologies. The first discovery is related to the protective role of TAp63 on premature aging. TAp63 controls skin homeostasis by maintaining dermal and epidermal progenitor/stem cell pool and protecting them from senescence, DNA damage and genomic instability. The second study is related to the role of TAp63, expressed by the primitive endoderm, on heart development. This unexpected role for TAp63 has been discovered by manipulation of embryonic stem cells in vitro and confirmed by the severe cardiomyopathy observed in brdm2 p63-null embryonic hearts. Interestingly, in both cases, TAp63 acts in a cell-nonautonomous manner on adjacent cells. Here, we discuss these findings and their potential connection during development.

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Hacking cell differentiation: transcriptional rerouting in reprogramming, lineage infidelity and metaplasia

Regalo

Leutz

2013

EMBO Mol Med

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Initiating neoplastic cell transformation events are of paramount importance for the comprehension of regeneration and vanguard oncogenic processes but are difficult to characterize and frequently clinically overlooked. In epithelia, pre-neoplastic transformation stages are often distinguished by the appearance of phenotypic features of another differentiated tissue, termed metaplasia. In haemato/lymphopoietic malignancies, cell lineage ambiguity is increasingly recorded. Both, metaplasia and biphenotypic leukaemia/lymphoma represent examples of dysregulated cell differentiation that reflect a history of trans-differentiation and/or epigenetic reprogramming. Here we compare the similarity between molecular events of experimental cell trans-differentiation as an emerging therapeutic concept, with lineage confusion, as in metaplasia and dysplasia forecasting tumour development.

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Transcriptional Network of p63 in Human Keratinocytes

Cited by 43 publications

References 56 publications

Mutant p53 subverts p63 control over KLF4 expression in keratinocytes

Mutant p53 subverts p63 control over KLF4 expression in keratinocytes

Regulation of skin aging and heart development by TAp63

Hacking cell differentiation: transcriptional rerouting in reprogramming, lineage infidelity and metaplasia

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