Transcriptional control of late differentiation in human keratinocytes by <scp>TA</scp>p63 and Notch

Koh, Li Fang; Ng, Boon Kiat; Bertrand, Juliette; Thierry, Françoise

doi:10.1111/exd.12764

Cited by 12 publications

(11 citation statements)

References 55 publications

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“…ΔN- and TAp63 have essential roles in epidermal differentiation, being associated with proliferation or cell cycle break/apoptosis, respectively 3 , 7 , 20 , 30 . A role for TAp63 in the transcriptional control of keratinocyte differentiation has been recently reported 29 . While the expression of ΔNp63 was not significantly modulated in DLX3-overexpressing human keratinocytes, we found significant modulation of a p63 target, NOXA 50 .…”

Section: Resultsmentioning

confidence: 99%

The homeoprotein DLX3 and tumor suppressor p53 co-regulate cell cycle progression and squamous tumor growth

et al. 2015

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Epidermal homeostasis depends on the coordinated control of keratinocyte cell cycle. Differentiation and the alteration of this balance can result in neoplastic development. Here we report on a novel DLX3-dependent network that constrains epidermal hyperplasia and squamous tumorigenesis. By integrating genetic and transcriptomic approaches, we demonstrate that DLX3 operates through a p53-regulated network. DLX3 and p53 physically interact on the p21 promoter to enhance p21 expression. Elevating DLX3 in keratinocytes produces a G1-S blockade associated with p53 signature transcriptional profiles. In contrast, DLX3 loss promotes a mitogenic phenotype associated with constitutive activation of ERK. DLX3 expression is lost in human skin cancers and is extinquished during progression of experimentally induced mouse squamous cell carcinoma (SCC). Reinstatement of DLX3 function is sufficient to attenuate the migration of SCC cells, leading to decreased wound closure. Our data establish the DLX3-p53 interplay as a major regulatory axis in epidermal differentiation and suggest that DLX3 is a modulator of skin carcinogenesis.

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Section: Resultsmentioning

confidence: 99%

The homeoprotein DLX3 and tumor suppressor p53 co-regulate cell cycle progression and squamous tumor growth

et al. 2015

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“…Initially, a reduced expression of Jagged1, NICD1, Notch1, Hes1, and Hey1 was evident as a result of KRT1 silencing, thereby demonstrating the downstream effects of inactivating the Notch pathway. Notch was previously suggested to be closely correlated with inducing the expression of skin differentiation markers, including KRT1 (Koh, Ng, Bertrand, & Thierry, ). Therefore, KRT1 expression increased as a result of upregulated Notch signaling (Totaro et al, ).…”

Section: Discussionmentioning

confidence: 98%

Retracted: Silencing of keratin 1 inactivates the Notch signaling pathway to inhibit renal interstitial fibrosis and glomerular sclerosis in uremia

Chen

Wang

Zhang

et al. 2019

Journal Cellular Physiology

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Renal interstitial fibrosis is a key factor in the development of chronic renal diseases, possibly leading to uremia. The present study conducted aimed to assess the hypothesis whether keratin 1 (KRT1) silencing could suppress kidney interstitial fibrosis and glomerular sclerosis via the Notch pathway to alleviate uremic symptoms. Differentially expressed genes associated with uremia were identified using the gene expression omnibus (GEO) database. Uremic rat models were established, in which short hairpin-RNA against KRT1, activators, and inhibitors of the Notch pathway were transfected. To further validate the mechanism of KRT1 in uremia, KRT1 expression, cell apoptosis, glomerular area

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“…Our results illustrate how chromatin connections to the lineage selector p63 are necessary and more likely to induce gene expression changes, but are not sufficient. Our finding that p63 at d7 is poised to act on later keratinocyte differentiation genes (Supplementary Table 2) 22,34,35 suggests the existence of additional inductive influences after addition of RA/BMP that will enable broader p63-dependent transcription. This is functionally similar to “poised” histone modifications and provides a structural explanation of how the order of morphogen exposure can determine downstream transcriptional programs.…”

mentioning

confidence: 92%

“…3d). Furthermore, d7 p63-independent genes connected to p63 include keratinocyte differentiation genes whose expression becomes p63-dependent later during keratinocyte maturation, including TP63 itself (Supplementary Table 2) 22,34,35 . These data suggest that p63 and morphogen-regulated chromatin connections foreshadow future gene action.…”

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confidence: 99%

Retinoic acid and BMP4 cooperate with p63 to alter chromatin dynamics during surface epithelial commitment

et al. 2018

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Human embryonic stem cell (hESC) differentiation promises advances in regenerative medicine 1 – 3 , yet conversion into transplantable tissues remains poorly understood. Using our keratinocyte differentiation system, we employ a multi-dimensional genomics approach to interrogate the contributions of inductive morphogens retinoic acid (RA) and bone morphogenetic protein 4 (BMP4) and the epidermal master regulator p63 4 , 5 during surface ectoderm commitment. In contrast to other master regulators 6 – 9 , p63 effects major transcriptional changes only after morphogens alter chromatin accessibility, establishing an epigenetic landscape for p63 to modify. p63 distally closes chromatin accessibility and promotes accumulation of H3K27me3 modifications. Cohesin HiChIP 10 visualizations of chromosome conformation reveal that p63 and the morphogens contribute to dynamic long-range chromatin interactions, as illustrated with TFAP2C regulation 11 . Our study demonstrates the unexpected dependency of p63 on morphogenetic signaling and provides novel insights into how a master regulator can specify diverse transcriptional programs based on the chromatin landscape induced by specific morphogen exposure.

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Transcriptional control of late differentiation in human keratinocytes by TAp63 and Notch

Abstract: We previously showed that in cervical carcinoma cells,

Cited by 12 publications

References 55 publications

The homeoprotein DLX3 and tumor suppressor p53 co-regulate cell cycle progression and squamous tumor growth

The homeoprotein DLX3 and tumor suppressor p53 co-regulate cell cycle progression and squamous tumor growth

Retracted: Silencing of keratin 1 inactivates the Notch signaling pathway to inhibit renal interstitial fibrosis and glomerular sclerosis in uremia

Retinoic acid and BMP4 cooperate with p63 to alter chromatin dynamics during surface epithelial commitment

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