Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation
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ABSTRACT:
PROVIDER: PRJNA96431 | ENA |
REPOSITORIES: ENA
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Project description:Notch signaling promotes commitment of keratinocytes to differentiation and suppresses tumorigenesis. p63, a p53 family member, has been implicated in establishment of the keratinocyte cell fate and/or maintenance of epithelial self-renewal. Here we show that p63 expression is suppressed by Notch1 activation in both mouse and human keratinocytes through a mechanism independent of cell cycle withdrawal and requiring down-modulation of selected interferon-responsive genes, including IRF7 and/or IRF3. In turn, elevated p63 expression counteracts the ability of Notch1 to restrict growth and promote differentiation. p63 functions as a selective modulator of Notch1-dependent transcription and function, with the Hes-1 gene as one of its direct negative targets. Thus, a complex cross-talk between Notch and p63 is involved in the balance between keratinocyte self-renewal and differentiation. Keywords: Notch1, p63, keratinocyte differentiation, gene expression profiling
2006-07-08 | GSE5229 | GEO
Project description:Notch signaling promotes commitment of keratinocytes to differentiation and suppresses tumorigenesis. p63, a p53 family member, has been implicated in establishment of the keratinocyte cell fate and/or maintenance of epithelial self-renewal. Here we show that p63 expression is suppressed by Notch1 activation in both mouse and human keratinocytes through a mechanism independent of cell cycle withdrawal and requiring down-modulation of selected interferon-responsive genes, including IRF7 and/or IRF3. In turn, elevated p63 expression counteracts the ability of Notch1 to restrict growth and promote differentiation. p63 functions as a selective modulator of Notch1-dependent transcription and function, with the Hes-1 gene as one of its direct negative targets. Thus, a complex cross-talk between Notch and p63 is involved in the balance between keratinocyte self-renewal and differentiation. Experiment Overall Design: PolyA+ mRNA (2-5 ug) from cells infected with the Ad GFP and Ad-NotchIC viruses was used as template for double stranded cDNA preparations with a T7-(dT)24 oligonucleotide primers for the first strand reaction. The resulting cDNA was used for preparation of biotin-labeled antisense cRNA and further used for hybridization to Affymetrix U74A or U95A âgene chipsâ according to the manufacturerâs recommendation.
2008-06-13 | E-GEOD-5229 | biostudies-arrayexpress
Project description:Here we characterized the transcriptome and epigenome of control keratinocytes during differentiation. Epigenomic analyses showed that the temporal enrichment of p63 motifs in dynamic enhancers underscores the key role of p63 in orchestrating the enhancer landscape during keratinocyte differentiation. The cooperation between p63 and its co-regulating factors, such as RUNX1, is important for the finetuning of gene expression.
2018-12-18 | GSE98483 | GEO
Project description:The epigenetic landscape controlled by p63 during epidermal keratinocyte differentiation
| PRJNA504358 | ENA
Project description:The epigenetic landscape controlled by p63 during epidermal keratinocyte differentiation
| PRJNA504359 | ENA
Project description:Skin toxicity is a frequently observed side effect in the era of "molecularly targeted therapies". Skin toxicity following administration of protein kinase inhibitors such as sorafenib, regorafenib, lapatinib, sunitinib, and others can be debilitating to the patient, resulting in dose reduction and discontinuation of treatment. The mechanisms of skin toxicity induced by targeted chemotherapy, such as sorafenib or regorafenib, are poorly understood. Further research is warranted to better understand the pathophysiology of drug-related skin toxicity in this setting and develop correction strategies. This study tests the hypothesis that sorafenib and regorafenib interfere with p63 expression and keratinocyte differentiation and skin remodeling.
Eligible study participants will be evaluated clinically for evidence of skin toxicity during their visits to the outpatient Oncology clinics. Study participants will undergo skin biopsies before sorafenib or regorafenib treatment is initiated and once rash develops or 12 weeks into treatment with sorafenib or regorafenib. Skin biopsies will be performed in Oncology clinics by the study investigators and clinic support staff.
Study participants will undergo both skin biopsies regardless of whether they develop a rash. In patients who develop a rash the most representative lesion will be biopsied. A normal appearing area of skin will be biopsied in participants who do not develop a rash.
| 2115273 | ecrin-mdr-crc
Project description:To determine if fibroblasts could be reprogrammed to a keratinocyte phenotype p63+KLF4 or LacZ expressing retroviruses were transduced into primary human neonatal fibroblasts. Global gene expression profiling using U133 plus 2.0 arrays were used to deteremine the extent of reprogramming to a keratinocyte phenoypte upon transduction with p63+KLF4. Fibroblasts transduced with p63+KLF4 were also treated +/- high calcium to determine if treatment with calcium could induce differentiation of these cells. Microarray analysis was also performed on cells treated +/- calcium. For gene expression profiling, cultured human fibroblasts were infected with LacZ or p63+KLF4 expressing retroviruses. p63+KLF4 cells were also treated +/- calcium. Microarray analysis using Affymetrix HG-U133 2.0 plus arrays was performed on duplicate samples.
2013-11-03 | E-GEOD-47746 | biostudies-arrayexpress
Project description:p63, a homologue of the tumor suppressor p53, is critical for the development and maintenance of squamous epithelia. p63 is specifically expressed in the basal layers of stratified epithelial tissues and is considered a specific marker for cells of this type. The role of p63 in tumorigenesis remains poorly defined. Numerous studies have highlighted the oncogenic potential of the predominant p63 isoform DeltaNp63alpha; however, data suggest that other p63 proteins can act as tumor suppressors or alter the metastatic potential of tumors. DeltaNp63alpha can act as a transcriptional repressor, but the link between the transcriptional functions of p63 and its biological role is still unclear. In this study, we used a loss-of-function approach to investigate the transcriptional programs controlled by p63. Disruption of p63 in squamous cell lines resulted in down-regulation of transcripts specifically expressed in squamous tissues and a significant alteration of keratinocyte differentiation. Interestingly, we found that disruption of p63 led to up-regulation of markers of nonepithelial tissues (mesenchyme and neural tissue) in both primary and immortalized squamous cells. Many of these up-regulated genes are associated with increased capacity for invasion and metastasis in tumors. Furthermore, loss of p63 expression was accompanied by a shift toward mesenchymal morphology and an increase in motility in primary keratinocytes and squamous cell lines. We conclude that loss of endogenous p63 expression results in up-regulation of genes associated with invasion and metastasis, and predisposes to a loss of epithelial and acquisition of mesenchymal characteristics. These findings have implications for the role of p63 in both development and tumorigenesis.
2007-11-11 | E-GEOD-4975 | biostudies-arrayexpress
Project description:To determine if fibroblasts could be reprogrammed to a keratinocyte phenotype p63+KLF4 or LacZ expressing retroviruses were transduced into primary human neonatal fibroblasts. Global gene expression profiling using U133 plus 2.0 arrays were used to deteremine the extent of reprogramming to a keratinocyte phenoypte upon transduction with p63+KLF4. Fibroblasts transduced with p63+KLF4 were also treated +/- high calcium to determine if treatment with calcium could induce differentiation of these cells. Microarray analysis was also performed on cells treated +/- calcium.
2013-11-03 | GSE47746 | GEO
Project description:Tightly controlled gene expression orchestrated by the transcription factor p63 during epithelial differentiation is important for development of epithelial-related structures such as epidermis, limb and craniofacial regions. How p63 regulates spatial and temporal expression of its target genes during these developmental processes is however not yet clear. By epigenomics profiling in stem cells established from one of these epithelial structures, the epidermis, we provide a global map of p63-bound regulatory elements that are categorized as single enhancers and clustered enhancers during epidermal differentiation. Transcriptomics analysis shows dynamic gene expression patterns during epidermal differentiation that correlates with the activity of p63-bound enhancers rather than with p63 binding itself. Only a subset of p63-bound enhancers is active in epidermal stem cells, and inactive p63-bound enhancers appear to function in gene regulation during the development of other epithelial tissues. Our data suggest a paradigm that p63 bookmarks genomic loci during the commitment of the epithelial lineage and regulates gene expression in different epithelial tissues through tissue-specific active enhancers. The catalogue of differentially expressed epidermal genes including non-coding RNAs and epithelial enhancers reported here provides a rich resource for studies of epithelial development and related diseases. Comparison of gene expression at different stages of keratinocyte differentiation
2015-05-01 | E-GEOD-59822 | biostudies-arrayexpress