{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T14:35:00Z","timestamp":1788186900983,"version":"build-2803163510"},"reference-count":52,"publisher":"Springer Science and Business Media LLC","issue":"8","license":[{"start":{"date-parts":[[2020,8,13]],"date-time":"2020-08-13T00:00:00Z","timestamp":1597276800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,8,13]],"date-time":"2020-08-13T00:00:00Z","timestamp":1597276800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP18ek0109241)"],"award-info":[{"award-number":["JP18ek0109241)"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"MEXT | Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["17H04223"],"award-info":[{"award-number":["17H04223"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"MEXT | Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["18K07811"],"award-info":[{"award-number":["18K07811"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Costello syndrome is an autosomal dominant disorder that is caused by germline <jats:italic>HRAS<\/jats:italic> mutations. Patients with Costello syndrome present craniofacial abnormalities, cardiac defects, and cancer predisposition, as well as skin abnormalities, including papillomas, keratosis pilaris, and eczematous dermatitis. However, the mechanisms underlying the dermatological abnormalities remain unclear. Here, we demonstrated that knock-in mice expressing an <jats:italic>Hras<\/jats:italic> G12S mutation (<jats:italic>Hras<\/jats:italic><jats:sup><jats:italic>G12S\/+<\/jats:italic><\/jats:sup> mice) are susceptible to develop atopic dermatitis (AD)-like skin lesions, including eczema, pruritus, elevated serum IgE levels, acanthosis, and the infiltration of mast cells, basophils, and type-2 innate lymphoid cells in the dermis, after stimulation with house dust mite allergens (<jats:italic>Dermatophagoides farinae<\/jats:italic>, Dfb). Reduced skin barrier function, increased proliferation of phosphorylated ERK (p-ERK)-positive epidermal cells, and increased Th2-type cytokines as well as epithelial cell-derived cytokines, including IL-33, were observed in the skin tissue of <jats:italic>Hras<\/jats:italic><jats:sup><jats:italic>G12S\/+<\/jats:italic><\/jats:sup> mice compared with <jats:italic>Hras<\/jats:italic><jats:sup>+\/+<\/jats:sup> mice. Cultured <jats:italic>Hras<\/jats:italic><jats:sup><jats:italic>G12S\/+<\/jats:italic><\/jats:sup> keratinocytes exhibited increased IL-33 expression after Dfb stimulation. PD0325901, an MEK inhibitor, ameliorated AD-like symptoms in <jats:italic>Hras<\/jats:italic><jats:sup><jats:italic>G12S\/+<\/jats:italic><\/jats:sup> mice, showing decreased proliferation of p-ERK-positive epidermal cells and decreased expression of IL-33. Our findings indicate that the epidermis of <jats:italic>Hras<\/jats:italic><jats:sup><jats:italic>G12S\/+<\/jats:italic><\/jats:sup> mice stimulated by Dfb strongly induced IL-33 expression and type-2 innate lymphoid cells, resulting in AD-like skin lesions. These results suggest that the epidermis of <jats:italic>Hras<\/jats:italic><jats:sup><jats:italic>G12S\/+<\/jats:italic><\/jats:sup> mice are prone to development of eczematous dermatitis stimulated with house dust mite allergens.<\/jats:p>","DOI":"10.1038\/s41419-020-02845-8","type":"journal-article","created":{"date-parts":[[2020,8,13]],"date-time":"2020-08-13T19:03:01Z","timestamp":1597345381000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Costello syndrome model mice with a Hras G12S mutation are susceptible to develop house dust mite-induced atopic dermatitis"],"prefix":"10.1038","volume":"11","author":[{"given":"Yu","family":"Katata","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shin-ichi","family":"Inoue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsuko","family":"Asao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuhei","family":"Kobayashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitoshi","family":"Terui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aya","family":"Inoue-Shibui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6580-3734","authenticated-orcid":false,"given":"Taiki","family":"Abe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuya","family":"Niihori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Setsuya","family":"Aiba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoto","family":"Ishii","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeo","family":"Kure","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoko","family":"Aoki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,8,13]]},"reference":[{"key":"2845_CR1","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1038\/nrm2636","volume":"10","author":"C Blanpain","year":"2009","unstructured":"Blanpain, C. & Fuchs, E. Epidermal homeostasis: a balancing act of stem cells in the skin. Nat. Rev. Mol. Cell Biol. 10, 207\u2013217 (2009).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2845_CR2","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1038\/nrc1097","volume":"3","author":"M Malumbres","year":"2003","unstructured":"Malumbres, M. & Barbacid, M. RAS oncogenes: the first 30 years. Nat. Rev. Cancer 3, 459\u2013465 (2003).","journal-title":"Nat. Rev. Cancer"},{"key":"2845_CR3","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1152\/physrev.2001.81.1.153","volume":"81","author":"Y Takai","year":"2001","unstructured":"Takai, Y., Sasaki, T. & Matozaki, T. Small GTP-binding proteins. Physiol. Rev. 81, 153\u2013208 (2001).","journal-title":"Physiol. Rev."},{"key":"2845_CR4","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1038\/sj.bjc.6606009","volume":"104","author":"F Kern","year":"2011","unstructured":"Kern, F., Niault, T. & Baccarini, M. Ras and Raf pathways in epidermis development and carcinogenesis. Br. J. Cancer 104, 229\u2013234 (2011).","journal-title":"Br. J. Cancer"},{"key":"2845_CR5","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1172\/JCI57415","volume":"122","author":"V Ratushny","year":"2012","unstructured":"Ratushny, V., Gober, M. D., Hick, R., Ridky, T. W. & Seykora, J. T. From keratinocyte to cancer: the pathogenesis and modeling of cutaneous squamous cell carcinoma. J. Clin. Invest. 122, 464\u2013472 (2012).","journal-title":"J. Clin. Invest."},{"key":"2845_CR6","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1016\/j.jaad.2012.04.008","volume":"67","author":"EY Chu","year":"2012","unstructured":"Chu, E. Y. et al. Diverse cutaneous side effects associated with BRAF inhibitor therapy: a clinicopathologic study. J. Am. Acad. Dermatol. 67, 1265\u20131272 (2012).","journal-title":"J. Am. Acad. Dermatol."},{"key":"2845_CR7","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1146\/annurev-genom-091212-153523","volume":"14","author":"KA Rauen","year":"2013","unstructured":"Rauen, K. A. The RASopathies. Annu. Rev. Genomics Hum. Genet. 14, 355\u2013369 (2013).","journal-title":"Annu. Rev. Genomics Hum. Genet."},{"key":"2845_CR8","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.gde.2009.04.001","volume":"19","author":"WE Tidyman","year":"2009","unstructured":"Tidyman, W. E. & Rauen, K. A. The RASopathies: developmental syndromes of Ras\/MAPK pathway dysregulation. Curr. Opin. Genet. Dev. 19, 230\u2013236 (2009).","journal-title":"Curr. Opin. Genet. Dev."},{"key":"2845_CR9","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/jhg.2015.114","volume":"61","author":"Y Aoki","year":"2016","unstructured":"Aoki, Y., Niihori, T., Inoue, S. & Matsubara, Y. Recent advances in RASopathies. J. Hum. Genet. 61, 33\u201339 (2016).","journal-title":"J. Hum. Genet."},{"key":"2845_CR10","doi-asserted-by":"crossref","first-page":"1725","DOI":"10.1002\/ajmg.a.61270","volume":"179","author":"KW Gripp","year":"2019","unstructured":"Gripp, K. W. et al. Costello syndrome: clinical phenotype, genotype, and management guidelines. Am. J. Med. Genet. A 179, 1725\u20131744 (2019).","journal-title":"Am. J. Med. Genet. A"},{"key":"2845_CR11","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1038\/ng1641","volume":"37","author":"Y Aoki","year":"2005","unstructured":"Aoki, Y. et al. Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat. Genet. 37, 1038\u20131040 (2005).","journal-title":"Nat. Genet."},{"key":"2845_CR12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/ajmg.a.31047","volume":"140","author":"KW Gripp","year":"2006","unstructured":"Gripp, K. W. et al. HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation. Am. J. Med. Genet. A 140, 1\u20137 (2006).","journal-title":"Am. J. Med. Genet. A"},{"key":"2845_CR13","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.ebiom.2017.11.029","volume":"27","author":"D Oba","year":"2018","unstructured":"Oba, D. et al. Mice with an oncogenic HRAS mutation are resistant to high-fat diet-induced obesity and exhibit impaired hepatic energy homeostasis. EBioMedicine 27, 138\u2013150 (2018).","journal-title":"EBioMedicine"},{"key":"2845_CR14","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1016\/j.jaci.2014.06.014","volume":"134","author":"JP Thyssen","year":"2014","unstructured":"Thyssen, J. P. & Kezic, S. Causes of epidermal filaggrin reduction and their role in the pathogenesis of atopic dermatitis. J. Allergy Clin. Immunol. 134, 792\u2013799 (2014).","journal-title":"J. Allergy Clin. Immunol."},{"key":"2845_CR15","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1016\/j.jaci.2010.10.018","volume":"127","author":"A De Benedetto","year":"2011","unstructured":"De Benedetto, A. et al. Tight junction defects in patients with atopic dermatitis. J. Allergy Clin. Immunol. 127, 773\u2013786.e771-777 (2011).","journal-title":"J. Allergy Clin. Immunol."},{"key":"2845_CR16","doi-asserted-by":"crossref","first-page":"E4061","DOI":"10.1073\/pnas.1525474113","volume":"113","author":"R Tokumasu","year":"2016","unstructured":"Tokumasu, R. et al. Dose-dependent role of claudin-1 in vivo in orchestrating features of atopic dermatitis. Proc. Natl Acad. Sci. USA 113, E4061\u2013E4068 (2016).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2845_CR17","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1254\/jphs.08332FP","volume":"109","author":"K Tsujii","year":"2009","unstructured":"Tsujii, K., Andoh, T., Ui, H., Lee, J.-B. & Kuraishi, Y. Involvement of tryptase and proteinase-activated receptor-2 in spontaneous itch-associated response in mice with atopy-like dermatitis. J. Pharmacol. Sci. 109, 388\u2013395 (2009).","journal-title":"J. Pharmacol. Sci."},{"key":"2845_CR18","doi-asserted-by":"crossref","first-page":"2683","DOI":"10.1172\/JCI67323","volume":"124","author":"M Kido-Nakahara","year":"2014","unstructured":"Kido-Nakahara, M. et al. Neural peptidase endothelin-converting enzyme 1 regulates endothelin 1-induced pruritus. J. Clin. Invest. 124, 2683\u20132695 (2014).","journal-title":"J. Clin. Invest."},{"key":"2845_CR19","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1159\/000473700","volume":"173","author":"Y Yamada","year":"2017","unstructured":"Yamada, Y. & Matsumoto, T. House dust mites induce production of endothelin-1 and matrix metalloproteinase-9 in keratinocytes via proteinase-activated receptor-2 activation. Int. Arch. Allergy Immunol. 173, 84\u201392 (2017).","journal-title":"Int. Arch. Allergy Immunol."},{"key":"2845_CR20","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1038\/sj.jid.5700965","volume":"128","author":"K Stefansson","year":"2008","unstructured":"Stefansson, K. et al. Activation of proteinase-activated receptor-2 by human kallikrein-related peptidases. J. Invest. Dermatol. 128, 18\u201325 (2008).","journal-title":"J. Invest. Dermatol."},{"key":"2845_CR21","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/j.immuni.2005.09.015","volume":"23","author":"J Schmitz","year":"2005","unstructured":"Schmitz, J. et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 23, 479\u2013490 (2005).","journal-title":"Immunity"},{"key":"2845_CR22","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.jdermsci.2013.02.001","volume":"70","author":"K Kabashima","year":"2013","unstructured":"Kabashima, K. New concept of the pathogenesis of atopic dermatitis: interplay among the barrier, allergy, and pruritus as a trinity. J. Dermatol. Sci. 70, 3\u201311 (2013).","journal-title":"J. Dermatol. Sci."},{"key":"2845_CR23","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1016\/j.alit.2016.12.002","volume":"66","author":"M Furue","year":"2017","unstructured":"Furue, M. et al. Atopic dermatitis: immune deviation, barrier dysfunction, IgE autoreactivity and new therapies. Allergol. Int. 66, 398\u2013403 (2017).","journal-title":"Allergol. Int."},{"key":"2845_CR24","first-page":"2169","volume":"118","author":"AJ Schuhmacher","year":"2008","unstructured":"Schuhmacher, A. J. et al. A mouse model for Costello syndrome reveals an Ang II-mediated hypertensive condition. J. Clin. Invest. 118, 2169\u20132179 (2008).","journal-title":"J. Clin. Invest."},{"key":"2845_CR25","first-page":"1535","volume":"7","author":"J Leon","year":"1987","unstructured":"Leon, J., Guerrero, I. & Pellicer, A. Differential expression of the ras gene family in mice. Mol. Cell Biol. 7, 1535\u20131540 (1987).","journal-title":"Mol. Cell Biol."},{"key":"2845_CR26","doi-asserted-by":"crossref","first-page":"4715","DOI":"10.1093\/hmg\/ddx354","volume":"26","author":"SI Inoue","year":"2017","unstructured":"Inoue, S. I. et al. Activated Braf induces esophageal dilation and gastric epithelial hyperplasia in mice. Hum. Mol. Genet. 26, 4715\u20134727 (2017).","journal-title":"Hum. Mol. Genet."},{"key":"2845_CR27","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1093\/hmg\/ddt455","volume":"23","author":"AF Goodwin","year":"2014","unstructured":"Goodwin, A. F. et al. Abnormal Ras signaling in Costello syndrome (CS) negatively regulates enamel formation. Hum. Mol. Genet. 23, 682\u2013692 (2014).","journal-title":"Hum. Mol. Genet."},{"key":"2845_CR28","volume":"7","author":"J Schreiber","year":"2017","unstructured":"Schreiber, J. et al. Mechanisms underlying cognitive deficits in a mouse model for Costello Syndrome are distinct from other RASopathy mouse models. Sci. Rep. 7, 1256 (2017).","journal-title":"Sci. Rep."},{"key":"2845_CR29","doi-asserted-by":"crossref","first-page":"E3806","DOI":"10.1073\/pnas.1619416114","volume":"114","author":"H Nakagawa","year":"2017","unstructured":"Nakagawa, H. et al. Biliary epithelial injury-induced regenerative response by IL-33 promotes cholangiocarcinogenesis from peribiliary glands. Proc. Natl Acad. Sci. USA 114, E3806\u2013E3815 (2017).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2845_CR30","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1089\/jir.2018.0044","volume":"39","author":"J Hong","year":"2019","unstructured":"Hong, J., Kim, S. & Lin, P. C. Interleukin-33 and ST2 signaling in tumor microenvironment. J. Interferon Cytokine Res. 39, 61\u201371 (2019).","journal-title":"J. Interferon Cytokine Res."},{"key":"2845_CR31","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.jdermsci.2019.08.006","volume":"96","author":"Y Imai","year":"2019","unstructured":"Imai, Y. Interleukin-33 in atopic dermatitis. J. Dermatol. Sci. 96, 2\u20137 (2019).","journal-title":"J. Dermatol. Sci."},{"key":"2845_CR32","doi-asserted-by":"crossref","first-page":"305","DOI":"10.2340\/00015555-2552","volume":"97","author":"U Nygaard","year":"2017","unstructured":"Nygaard, U. et al. The \u201calarmins\u201d HMBG1 and IL-33 downregulate structural skin barrier proteins and impair epidermal growth. Acta Derm. Venereol. 97, 305\u2013312 (2017).","journal-title":"Acta Derm. Venereol."},{"key":"2845_CR33","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.jdermsci.2018.02.017","volume":"90","author":"WI Ryu","year":"2018","unstructured":"Ryu, W. I. et al. IL-33 down-regulates CLDN1 expression through the ERK\/STAT3 pathway in keratinocytes. J. Dermatol. Sci. 90, 313\u2013322 (2018).","journal-title":"J. Dermatol. Sci."},{"key":"2845_CR34","doi-asserted-by":"crossref","first-page":"13921","DOI":"10.1073\/pnas.1307321110","volume":"110","author":"Y Imai","year":"2013","unstructured":"Imai, Y. et al. Skin-specific expression of IL-33 activates group 2 innate lymphoid cells and elicits atopic dermatitis-like inflammation in mice. Proc. Natl Acad. Sci. USA 110, 13921\u201313926 (2013).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2845_CR35","doi-asserted-by":"crossref","first-page":"2939","DOI":"10.1084\/jem.20130351","volume":"210","author":"M Salimi","year":"2013","unstructured":"Salimi, M. et al. A role for IL-25 and IL-33-driven type-2 innate lymphoid cells in atopic dermatitis. J. Exp. Med. 210, 2939\u20132950 (2013).","journal-title":"J. Exp. Med."},{"key":"2845_CR36","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1111\/imr.12552","volume":"278","author":"LY Drake","year":"2017","unstructured":"Drake, L. Y. & Kita, H. IL-33: biological properties, functions, and roles in airway disease. Immunol. Rev. 278, 173\u2013184 (2017).","journal-title":"Immunol. Rev."},{"key":"2845_CR37","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1086\/302829","volume":"66","author":"A Hinek","year":"2000","unstructured":"Hinek, A. et al. Decreased elastin deposition and high proliferation of fibroblasts from Costello syndrome are related to functional deficiency in the 67-kD elastin-binding protein. Am. J. Hum. Genet. 66, 859\u2013872 (2000).","journal-title":"Am. J. Hum. Genet."},{"key":"2845_CR38","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/ajmg.a.30495","volume":"133A","author":"A Hinek","year":"2005","unstructured":"Hinek, A. et al. Myocardial storage of chondroitin sulfate-containing moieties in Costello syndrome patients with severe hypertrophic cardiomyopathy. Am. J. Med. Genet. A 133A, 1\u201312 (2005).","journal-title":"Am. J. Med. Genet. A"},{"key":"2845_CR39","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.jdermsci.2010.01.004","volume":"58","author":"M Tarutani","year":"2010","unstructured":"Tarutani, M. et al. Neutrophil-dominant psoriasis-like skin inflammation induced by epidermal-specific expression of Raf in mice. J. Dermatol. Sci. 58, 28\u201335 (2010).","journal-title":"J. Dermatol. Sci."},{"key":"2845_CR40","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.jdermsci.2013.06.007","volume":"72","author":"M Tarutani","year":"2013","unstructured":"Tarutani, M., Nakajima, K., Takaishi, M., Ohko, K. & Sano, S. Epidermal hyperplasia induced by Raf-MAPK signaling requires Stat3 activation. J. Dermatol. Sci. 72, 110\u2013115 (2013).","journal-title":"J. Dermatol. Sci."},{"key":"2845_CR41","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1038\/ng.2316","volume":"44","author":"L Groesser","year":"2012","unstructured":"Groesser, L. et al. Postzygotic HRAS and KRAS mutations cause nevus sebaceous and Schimmelpenning syndrome. Nat. Genet. 44, 783\u2013787 (2012).","journal-title":"Nat. Genet."},{"key":"2845_CR42","doi-asserted-by":"crossref","first-page":"7979","DOI":"10.1073\/pnas.0900343106","volume":"106","author":"X Chen","year":"2009","unstructured":"Chen, X. et al. Endogenous expression of Hras(G12V) induces developmental defects and neoplasms with copy number imbalances of the oncogene. Proc. Natl Acad. Sci. USA 106, 7979\u20137984 (2009).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2845_CR43","doi-asserted-by":"crossref","first-page":"e14012","DOI":"10.7554\/eLife.14012","volume":"5","author":"J Raguz","year":"2016","unstructured":"Raguz, J. et al. Epidermal RAF prevents allergic skin disease. Elife 5, e14012 (2016).","journal-title":"Elife"},{"key":"2845_CR44","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1111\/pde.13057","volume":"34","author":"NV Marukian","year":"2017","unstructured":"Marukian, N. V., Levinsohn, J. L., Craiglow, B. G., Milstone, L. M. & Choate, K. A. Palmoplantar keratoderma in Costello syndrome responsive to acitretin. Pediatr. Dermatol. 34, 160\u2013162 (2017).","journal-title":"Pediatr. Dermatol."},{"key":"2845_CR45","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1111\/bjd.17077","volume":"180","author":"D Bessis","year":"2019","unstructured":"Bessis, D. et al. Dermatological manifestations in cardiofaciocutaneous syndrome: a prospective multicentric study of 45 mutation-positive patients. Br. J. Dermatol. 180, 172\u2013180 (2019).","journal-title":"Br. J. Dermatol."},{"key":"2845_CR46","doi-asserted-by":"crossref","first-page":"4642","DOI":"10.1158\/0008-5472.CAN-17-1925","volume":"78","author":"BR Untch","year":"2018","unstructured":"Untch, B. R. et al. Tipifarnib inhibits HRAS-driven dedifferentiated thyroid cancers. Cancer Res. 78, 4642\u20134657 (2018).","journal-title":"Cancer Res."},{"key":"2845_CR47","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.jdermsci.2016.02.002","volume":"82","author":"L Zhou","year":"2016","unstructured":"Zhou, L., Yang, K., Wickett, R. R., Andl, T. & Zhang, Y. Dermal sheath cells contribute to postnatal hair follicle growth and cycling. J. Dermatol. Sci. 82, 129\u2013131 (2016).","journal-title":"J. Dermatol. Sci."},{"key":"2845_CR48","doi-asserted-by":"crossref","first-page":"2237","DOI":"10.1016\/j.jacc.2019.01.066","volume":"73","author":"G Andelfinger","year":"2019","unstructured":"Andelfinger, G. et al. Hypertrophic cardiomyopathy in Noonan syndrome treated by MEK-inhibition. J. Am. Coll. Cardiol. 73, 2237\u20132239 (2019).","journal-title":"J. Am. Coll. Cardiol."},{"key":"2845_CR49","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1177\/1758834014566428","volume":"7","author":"SJ Welsh","year":"2015","unstructured":"Welsh, S. J. & Corrie, P. G. Management of BRAF and MEK inhibitor toxicities in patients with metastatic melanoma. Ther. Adv. Med. Oncol. 7, 122\u2013136 (2015).","journal-title":"Ther. Adv. Med. Oncol."},{"key":"2845_CR50","doi-asserted-by":"crossref","first-page":"6553","DOI":"10.1093\/hmg\/ddu376","volume":"23","author":"S Inoue","year":"2014","unstructured":"Inoue, S. et al. New BRAF knockin mice provide a pathogenetic mechanism of developmental defects and a therapeutic approach in cardio-facio-cutaneous syndrome. Hum. Mol. Genet. 23, 6553\u20136566 (2014).","journal-title":"Hum. Mol. Genet."},{"key":"2845_CR51","doi-asserted-by":"crossref","first-page":"139","DOI":"10.2332\/allergolint.O-06-458","volume":"56","author":"M Yamamoto","year":"2007","unstructured":"Yamamoto, M. et al. A novel atopic dermatitis model induced by topical application with dermatophagoides farinae extract in NC\/Nga mice. Allergol. Int. 56, 139\u2013148 (2007).","journal-title":"Allergol. Int."},{"key":"2845_CR52","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.4049\/jimmunol.1900188","volume":"203","author":"S Kobayashi","year":"2019","unstructured":"Kobayashi, S. et al. TNF receptor-associated factor 5 limits function of plasmacytoid dendritic cells by controlling IFN regulatory factor 5 expression. J. Immunol. 203, 1447\u20131456 (2019).","journal-title":"J. Immunol."}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-020-02845-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-020-02845-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-020-02845-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,5]],"date-time":"2022-12-05T14:57:18Z","timestamp":1670252238000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-020-02845-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,13]]},"references-count":52,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2020,8]]}},"alternative-id":["2845"],"URL":"https:\/\/doi.org\/10.1038\/s41419-020-02845-8","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,8,13]]},"assertion":[{"value":"18 March 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 July 2020","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 July 2020","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 August 2020","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"617"}}