Hitting the Numbers: The Emerging Network of p63 Targets

Viganò, M. Alessandra; Mantovani, Roberto

doi:10.4161/cc.6.3.3802

Cited by 39 publications

(40 citation statements)

References 73 publications

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“…Our data showing that KLF4 expression is increased upon in vitro differentiation-as p63 decreases-and that p63 represses KLF4 transcription are in line with the expression data; this effect is more pronounced in adult KCs compared with neonatal, and it is directly exerted by binding to upstream and downstream sites in the KLF4 promoter region. In general, the analysis of p63 targets derived either by expression profiling or by location analysis (reviewed by Perez and Pietenpol, 2007;Vigano`and Mantovani, 2007) has lent support to the idea that the TF is important in determining the proliferative potential of skin basal KCs (Senoo et al, 2007;Su et al, 2009): among activated targets, in particular, there are progrowth genes, whereas TFs involved in differentiation, such as c-Jun, C/EBPd and HBP1, are repressed. Pathways at the crossroad of these decisions, such as Notch, Wnt and SHH, are also controlled.…”

Section: P63 and Klf4 In Normal Skinmentioning

confidence: 99%

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: P63 and Klf4 In Normal Skinmentioning

confidence: 99%

Mutant p53 subverts p63 control over KLF4 expression in keratinocytes

et al. 2010

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“…Recently, Vigano' et al 74,77 identified high-confidence target genes for DNp63 using a genome-wide approach. They identified new categories of genes regulated by p63, among which are developmental, morphogenetic genes and those involved in tissue regeneration.…”

Section: Transcriptional Regulation By P63mentioning

confidence: 99%

TAp63 and ΔNp63 in Cancer and Epidermal Development

et al. 2007

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“…ChIP (chromatin immunoprecipitation)-on-chip is a high-throughput technique that identifies DNA sequences occupied by transcription factors and other DNA-binding proteins on a genome-wide scale. When combined with gene-expression analysis, ChIP-on-chip has proved to be a powerful tool for gaining insight into the key intracellular signaling pathways governed by specific factors [12][13][14]. Owing to concerns regarding ES cell line identity, several sets of cDNA microarray data from different ES cell lines and their derivatives have been collected and are publicly available [1,2].…”

Section: Introductionmentioning

confidence: 99%

Yamanaka factors critically regulate the developmental signaling network in mouse embryonic stem cells

et al. 2008

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npg Yamanaka factors (Oct3/4, Sox2, Klf4, c-Myc) are highly expressed in embryonic stem (ES) cells, and their overexpression can induce pluripotency in both mouse and human somatic cells, indicating that these factors regulate the developmental signaling network necessary for ES cell pluripotency. However, systemic analysis of the signaling pathways regulated by Yamanaka factors has not yet been fully described. In this study, we identified the target promoters of endogenous Yamanaka factors on a whole genome scale using ChIP (chromatin immunoprecipitation)-on-chip in E14.1 mouse ES cells, and we found that these four factors co-occupied 58 promoters. Interestingly, when Oct4 and Sox2 were analyzed as core factors, Klf4 functioned to enhance the core factors for development regulation, whereas c-Myc seemed to play a distinct role in regulating metabolism. The pathway analysis revealed that Yamanaka factors collectively regulate a developmental signaling network composed of 16 developmental signaling pathways, nine of which represent earlier unknown pathways in ES cells, including apoptosis and cellcycle pathways. We further analyzed data from a recent study examining Yamanaka factors in mouse ES cells. Interestingly, this analysis also revealed 16 developmental signaling pathways, of which 14 pathways overlap with the ones revealed by this study, despite that the target genes and the signaling pathways regulated by each individual Yamanaka factor differ significantly between these two datasets. We suggest that Yamanaka factors critically regulate a developmental signaling network composed of approximately a dozen crucial developmental signaling pathways to maintain the pluripotency of ES cells and probably also to induce pluripotent stem cells.

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Hitting the Numbers: The Emerging Network of p63 Targets

Cited by 39 publications

References 73 publications

Mutant p53 subverts p63 control over KLF4 expression in keratinocytes

Mutant p53 subverts p63 control over KLF4 expression in keratinocytes

TAp63 and ΔNp63 in Cancer and Epidermal Development

Yamanaka factors critically regulate the developmental signaling network in mouse embryonic stem cells

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