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

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 t...

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Autores principales: Corley, Susan M., Mendoza-Reinoso, Veronica, Giles, Nichole, Singer, Emma Suwanun, Common, John E., Wilkins, Marc R., Beverdam, Annemiek
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6208416/
https://www.ncbi.nlm.nih.gov/pubmed/30382077
http://dx.doi.org/10.1038/s41419-018-1141-5
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author Corley, Susan M.
Mendoza-Reinoso, Veronica
Giles, Nichole
Singer, Emma Suwanun
Common, John E.
Wilkins, Marc R.
Beverdam, Annemiek
author_facet Corley, Susan M.
Mendoza-Reinoso, Veronica
Giles, Nichole
Singer, Emma Suwanun
Common, John E.
Wilkins, Marc R.
Beverdam, Annemiek
author_sort Corley, Susan M.
collection PubMed
description 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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spelling pubmed-62084162018-10-31 Plau and Tgfbr3 are YAP-regulated genes that promote keratinocyte proliferation Corley, Susan M. Mendoza-Reinoso, Veronica Giles, Nichole Singer, Emma Suwanun Common, John E. Wilkins, Marc R. Beverdam, Annemiek Cell Death Dis Article 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. Nature Publishing Group UK 2018-10-31 /pmc/articles/PMC6208416/ /pubmed/30382077 http://dx.doi.org/10.1038/s41419-018-1141-5 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Corley, Susan M.
Mendoza-Reinoso, Veronica
Giles, Nichole
Singer, Emma Suwanun
Common, John E.
Wilkins, Marc R.
Beverdam, Annemiek
Plau and Tgfbr3 are YAP-regulated genes that promote keratinocyte proliferation
title Plau and Tgfbr3 are YAP-regulated genes that promote keratinocyte proliferation
title_full Plau and Tgfbr3 are YAP-regulated genes that promote keratinocyte proliferation
title_fullStr Plau and Tgfbr3 are YAP-regulated genes that promote keratinocyte proliferation
title_full_unstemmed Plau and Tgfbr3 are YAP-regulated genes that promote keratinocyte proliferation
title_short Plau and Tgfbr3 are YAP-regulated genes that promote keratinocyte proliferation
title_sort plau and tgfbr3 are yap-regulated genes that promote keratinocyte proliferation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6208416/
https://www.ncbi.nlm.nih.gov/pubmed/30382077
http://dx.doi.org/10.1038/s41419-018-1141-5
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