p63 Regulates Human Keratinocyte Proliferation via MYC-regulated Gene Network and Differentiation Commitment through Cell Adhesion-related Gene Network

Commissariat à l'Energie Atomique, Biologie à Grande Echelle, F-38054 Grenoble, France.
Journal of Biological Chemistry (Impact Factor: 4.57). 12/2011; 287(8):5627-38. DOI: 10.1074/jbc.M111.328120
Source: PubMed


Although p63 and MYC are important in the control of epidermal homeostasis, the underlying molecular mechanisms governing keratinocyte proliferation or differentiation downstream of these two genes are not completely understood. By analyzing the transcriptional changes and phenotypic consequences of the loss of either p63 or MYC in human developmentally mature keratinocytes, we have characterized the networks acting downstream of these two genes to control epidermal homeostasis. We show that p63 is required to maintain growth and to commit to differentiation by two distinct mechanisms. Knockdown of p63 led to down-regulation of MYC via the Wnt/β-catenin and Notch signaling pathways and in turn reduced keratinocyte proliferation. We demonstrate that a p63-controlled keratinocyte cell fate network is essential to induce the onset of keratinocyte differentiation. This network contains several secreted proteins involved in cell migration/adhesion, including fibronectin 1 (FN1), interleukin-1β (IL1B), cysteine-rich protein 61 (CYR61), and jagged-1 (JAG1), that act downstream of p63 as key effectors to trigger differentiation. Our results characterized for the first time a connection between p63 and MYC and a cell adhesion-related network that controls differentiation. Furthermore, we show that the balance between the MYC-controlled cell cycle progression network and the p63-controlled cell adhesion-related network could dictate skin cell fate.

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    • "Overexpression of p63 induced an increase in total b-catenin protein and a reduction in p-b-catenin. Consistent with our results, p63 regulates cell proliferation in human keratinocytes via a Myc-regulated gene network, and commitment to differentiation through a cell adhesion-related gene network [10]. The target genes of b-catenin are c-Myc and cyclin D1 (cell cycle-regulating genes) and MMP-7 and uPA (genes related to the metastasis and invasion of cancer cells) [31] [32]. "
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    ABSTRACT: The development of esophageal squamous carcinomas (ESC) results from numerous genetic alterations. Our previous study demonstrated that p63 is highly expressed in human ESC cells and stimulates their growth; however, the mechanism by which p63 regulates ESC cell adhesion and invasion remains unclear. In the present study, we further elucidated the underlying molecular mechanisms by which p63 regulates metastasis in ESC cells. Knockdown of p63 significantly diminished the invasion of ESC cell lines TE-8 and TE-12, whereas overexpression of p63 significantly increased the migration rates of BE3 and OE33 cells. The mRNA and protein levels of vimentin, twist, SUSD2, and uPA were significantly decreased in p63-knockdown ESC cells, while overexpression of p63 induced an increase in vimentin, SUSD2, and uPA. In addition, knockdown of p63 in ESC cells significantly reduced levels of β-catenin and c-Myc, while overexpression of p63 increased β-catenin, but reduced p-β-catenin level. Therefore, p63 regulates the migration and invasion of ESC cells through activation of the β-catenin/c-Myc pathway. Our results suggest that targeting p63 may constitute a potential therapeutic strategy for ESC.
    Cancer Letters 10/2014; 353(1). DOI:10.1016/j.canlet.2014.07.016 · 5.62 Impact Factor
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    • "Although the importance of p63 in epidermal stratification during development [27] and in the commitment to differentiation of developmentally mature keratinocytes [6], [7] has been clearly established, the potential role of p63-regulated miRNAs in these functions remained mostly unknown. In this paper, we elucidate the role of p63-regulated, MAPK-targeting miRNAs in the onset of human keratinocyte differentiation. "
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    ABSTRACT: The p63 protein plays a key role in regulating human keratinocyte proliferation and differentiation. Although some p63-regulating microRNAs (miRNAs) have been identified in the control of epidermal homeostasis, little is known about miRNAs acting downstream of p63. In this paper, we characterized multiple p63-regulated miRNAs (miR-17, miR-20b, miR-30a, miR-106a, miR-143 and miR-455-3p) and elucidated their roles in the onset of keratinocyte differentiation. We identified RB, p21 and multiple MAPKs as targets of these p63-controlled miRNAs. Upon inhibition of most of these miRNAs, we observed defects in commitment to differentiation that could be reversed by siRNA-mediated silencing of their targets. Furthermore, knockdown of MAPK8 and MAPK9 efficiently restored expression of the early differentiation markers keratin 1 and keratin 10 in p63-silenced primary human keratinocytes. These results highlight new mechanistic roles of multiple miRNAs, particularly the miR-17 family (miR-17, miR-20b and miR-106a), as regulatory intermediates for coordinating p63 with MAPK signaling in the commitment of human mature keratinocytes to early differentiation.
    PLoS ONE 09/2012; 7(9):e45761. DOI:10.1371/journal.pone.0045761 · 3.23 Impact Factor
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    ABSTRACT: Notch signaling is critical for proper heart development and recently has been reported to participate in adult cardiac repair. Notch resides at the cell surface as a single pass transmembrane receptor, transits through the cytoplasm following activation, and acts as a transcription factor upon entering the nucleus. This dynamic and widespread cellular distribution allows for potential interactions with many signaling and binding partners. Notch displays temporal as well as spatial versatility, acting as a strong developmental signal, controlling cell fate determination and lineage commitment, and playing a pivotal role in embryonic and adult stem cell proliferation and differentiation. This review serves as an update of recent literature addressing Notch signaling in the heart, with attention to findings from noncardiac research that provide clues for further interpretation of how the Notch pathway influences cardiac biology. Specific areas of focus include Notch signaling in adult myocardium following pathologic injury, the role of Notch in cardiac progenitor cells with respect to differentiation and cardiac repair, crosstalk between Notch and other cardiac signaling pathways, and emerging aspects of noncanonical Notch signaling in heart.
    Journal of Molecular and Cellular Cardiology 03/2012; 52(6):1226-32. DOI:10.1016/j.yjmcc.2012.03.007 · 4.66 Impact Factor
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