Epidermal YAP activity drives canonical WNT16/β-catenin signaling to promote keratinocyte proliferation in vitro and in the murine skin

Mendoza-Reinoso, Veronica; Beverdam, Annemiek

doi:10.1016/j.scr.2018.03.005

Cited by 28 publications

(18 citation statements)

References 54 publications

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“…The bases for tissue development and homeostasis reside in the proliferation of stem and progenitor cells, and our data pointed to an aberrant proliferation mechanism. Indeed, some of the genes that were found to be downregulated, such as Igfbp3, Wnt6, and Nfatc1, have previously been linked to keratinocytes proliferation in vivo (Edmondson et al, 2005;Horsley et al, 2008;Mendoza-Reinoso and Beverdam, 2018). Conversely, in other reports, K15 expression was suppressed in nonhomeostatic, hyperproliferating conditions, such as in psoriatic tissues or during wound healing (Jia et al, 2016;Porter et al, 2000;Waseem et al, 1999).…”

Section: How Progerin Expression Induces Defects In Molecular Andmentioning

confidence: 97%

Accumulation of Progerin Affects the Symmetry of Cell Division and Is Associated with Impaired Wnt Signaling and the Mislocalization of Nuclear Envelope Proteins

Sola-Carvajal

Revêchon

Helgadottir

et al. 2019

Journal of Investigative Dermatology

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Hutchinson-Gilford progeria syndrome (HGPS) is the result of a defective form of the lamin A protein called progerin. While progerin is known to disrupt the properties of the nuclear lamina, the underlying mechanisms responsible for the pathophysiology of HGPS remain less clear. Previous studies in our laboratory have shown that progerin expression in murine epidermal basal cells results in impaired stratification and halted development of the skin. Stratification and differentiation of the epidermis is regulated by asymmetric stem cell division. Here, we show that expression of progerin impairs the ability of stem cells to maintain tissue homeostasis as a result of altered cell division. Quantification of basal skin cells showed an increase in symmetric cell division that correlated with progerin accumulation in HGPS mice. Investigation of the mechanisms underlying this phenomenon revealed a putative role of Wnt/b-catenin signaling. Further analysis suggested an alteration in the nuclear translocation of b-catenin involving the inner and outer nuclear membrane proteins, emerin and nesprin-2. Taken together, our results suggest a direct involvement of progerin in the transmission of Wnt signaling and normal stem cell division. These insights into the molecular mechanisms of progerin may help develop new treatment strategies for HGPS.In situ hybridization K15 transcripts were detected using RNAscope (Advanced Cell Diagnostic, Newark, CA) in accordance with the manufacturer's protocol. Few modifications were made: target A Sola-Carvajal et al.

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Section: How Progerin Expression Induces Defects In Molecular Andmentioning

confidence: 97%

Accumulation of Progerin Affects the Symmetry of Cell Division and Is Associated with Impaired Wnt Signaling and the Mislocalization of Nuclear Envelope Proteins

Sola-Carvajal

Revêchon

Helgadottir

et al. 2019

Journal of Investigative Dermatology

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“…Finally, Wnt signaling also appears to cooperate with YAP/TAZ in other tissues, such as skin. [ 270,271 ]…”

Section: Introductionmentioning

confidence: 99%

YAP/TAZ: Drivers of Tumor Growth, Metastasis, and Resistance to Therapy

2020

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The transcriptional co-activators YAP (or YAP1) and TAZ (or WWTR1) are frequently activated during the growth and progression of many solid tumors, including lung, colorectal, breast, pancreatic, and liver carcinomas as well as melanoma and glioma. YAP/TAZ bind to TEAD-family co-activators to drive cancer cell survival, proliferation, invasive migration, and metastasis. YAP/TAZ activation may also confer resistance to chemotherapy, radiotherapy, or immunotherapy. YAP-TEAD cooperates with the RAS-induced AP-1 (FOS/JUN) transcription factor to drive tumor growth and cooperates with MRTF-SRF to promote activation of cancer-associated fibroblasts, matrix stiffening, and metastasis. The key upstream repressor of YAP/TAZ activation is the Hippo (MST1/2-LATS1/2) pathway and the key upstream activators are mechanically induced Integrin-SRC and E-cadherin-AJUBA/TRIP6/LIMD1, growth factor induced PI3K-AKT, and inflammation-induced G-protein coupled receptor (GPCR) signals, all of which antagonize the Hippo pathway. In this review, strategies to target YAP/TAZ activity in cancer are discussed along with the prospects for synergy with established pillars of cancer therapy.

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“…These mice express a mildly dominant active YAP mutant protein in basal Keratin5/14-positive keratinocytes, leading to severe skin abnormalities, including epidermal hyperplasia, progressive dorsal alopecia due to abnormal hair follicles, loss of whiskers and dry, scaly skin 5 . These abnormalities are caused by increased proliferation of the basal stem/progenitor cell populations displaying high nuclear β-catenin and GLI2 activity 5 – 8 . There were however no signs of tumour formation in the skin of YAP2-5SA-∆C mice 5 .…”

Section: Introductionmentioning

confidence: 99%

Plau and Tgfbr3 are YAP-regulated genes that promote keratinocyte proliferation

et al. 2018

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Yes-associated protein (YAP) is a mechanosensor protein and a downstream effector of the Hippo kinase pathway, which controls organ growth, cell proliferation, survival, maintenance and regeneration. Unphosphorylated YAP translocates to the nucleus where it acts as a cofactor of primarily the TEAD transcription factors to activate target gene transcription and cell proliferation. Perturbed YAP activation results in tumorigenesis. The pathways downstream of activated YAP that drive cell proliferation remain relatively unexplored. In this study, we employed YAP2-5SA-∆C transgenic mice, which overexpress a mildly activated YAP mutant protein in basal keratinocytes leading to increased proliferation of the epidermal stem/progenitor cell populations. We performed massively-parallel sequencing of skin biopsy mRNA (RNA-Seq) and found dysregulation of 1491 genes in YAP2-5SA-∆C skin, including many with roles in cell activation and proliferation. Furthermore, we found that 150 of these dysregulated genes harbored YAP/TEAD binding motifs in the 3′ UTR, suggesting that these may be direct YAP/TEAD target genes in the control of epidermal regeneration. Further validation and functional characterization assays identified Plau and Tgfbr3 as prime candidate genes that may be activated by epidermal YAP activity in the mouse skin in vivo to promote keratinocyte proliferation. This study provides novel insights into the mechanisms regulated by YAP that control tissue homeostasis, and in particular in conditions where YAP is aberrantly activated such as in neoplastic and regenerative skin disease.

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Epidermal YAP activity drives canonical WNT16/β-catenin signaling to promote keratinocyte proliferation in vitro and in the murine skin

Cited by 28 publications

References 54 publications

Accumulation of Progerin Affects the Symmetry of Cell Division and Is Associated with Impaired Wnt Signaling and the Mislocalization of Nuclear Envelope Proteins

Accumulation of Progerin Affects the Symmetry of Cell Division and Is Associated with Impaired Wnt Signaling and the Mislocalization of Nuclear Envelope Proteins

YAP/TAZ: Drivers of Tumor Growth, Metastasis, and Resistance to Therapy

Plau and Tgfbr3 are YAP-regulated genes that promote keratinocyte proliferation

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