{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:20:34Z","timestamp":1790742034636,"version":"4.1.0"},"reference-count":35,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2016,3,1]],"date-time":"2016-03-01T00:00:00Z","timestamp":1456790400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Nature Science Foundation of China","doi-asserted-by":"publisher","award":["81472905"],"award-info":[{"award-number":["81472905"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Nature Science Foundation of China","doi-asserted-by":"publisher","award":["81472872"],"award-info":[{"award-number":["81472872"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Nature Science Foundation of China","doi-asserted-by":"publisher","award":["81101207"],"award-info":[{"award-number":["81101207"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Peking Union Medical College Youth Research Fund","award":["33320140048"],"award-info":[{"award-number":["33320140048"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,3,1]]},"abstract":"<jats:title>Summary<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Acne inversa (AI) is a chronic inflammatory skin disease with an autosomal dominant inheritance pattern. Mutations of the gene encoding nicastrin (NCSTN), a cofactor subunit of \u03b3-secretase, are responsible for familial AI. However, whether deficiency of nicastrin is functionally implicated in the biological behaviours of human keratinocytes and related molecular mechanisms remains unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To study alterations of biological traits and related signalling pathways modulated by nicastrin knockdown in keratinocytes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A human immortalized keratinocyte cell line (HaCaT) was treated with efficient small interfering (si)RNA-targeted NCSTN. Cell proliferation was measured by CCK-8 assay; cell-cycle and cell apoptosis analyses were detected by flow cytometry. Microarray analysis was applied to uncover impacts of NCSTN silencing on whole-genome expression of HaCaT cells. Altered signalling pathways were further confirmed by real-time polymerase chain reaction, Western blotting and immunohistochemistry in both HaCaT cells and lesions of a patient with AI with NCSTN mutation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>NCSTN knockdown in HaCaT cells impaired \u03b3-secretase activity, leading to increased cell proliferation and S-phase population. Microarray data also showed that numerous genes and pathways implicated in proliferation and differentiation of keratinocytes were statistically changed. Among these genes, expression levels of several Notch pathway molecules, known as \u03b3-secretase substrates, were validated to be significantly attenuated in both nicastrin-silencing HaCaT cells and the lesion of the patient. Furthermore, a remarkable elevation of expression of phosphoinositide 3-kinase (PI3K), AKT and its activated form pAKT was illustrated in siRNA-treated HaCaT cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Deficiency of the NCSTN in familial AI may regulate proliferation and differentiation of keratinocytes mainly through the Notch and PI3K\/AKT signalling pathways.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bjd.14223","type":"journal-article","created":{"date-parts":[[2015,10,16]],"date-time":"2015-10-16T11:06:34Z","timestamp":1444993594000},"page":"522-532","source":"Crossref","is-referenced-by-count":90,"title":["Nicastrin mutations in familial acne inversa impact keratinocyte proliferation and differentiation through the Notch and phosphoinositide 3-kinase\/AKT signalling pathways"],"prefix":"10.1093","volume":"174","author":[{"given":"X.","family":"Xiao","sequence":"first","affiliation":[{"name":"Institute of Dermatology Chinese Academy of Medical Sciences St 12 Jiangwangmiao Nanjing Jiangsu 210042 China"},{"name":"Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs St 12 Jiangwangmiao Nanjing Jiangsu 210042 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y.","family":"He","sequence":"additional","affiliation":[{"name":"Institute of Dermatology Chinese Academy of Medical Sciences St 12 Jiangwangmiao Nanjing Jiangsu 210042 China"},{"name":"Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs St 12 Jiangwangmiao Nanjing Jiangsu 210042 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Dermatology Chinese Academy of Medical Sciences St 12 Jiangwangmiao Nanjing Jiangsu 210042 China"},{"name":"Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs St 12 Jiangwangmiao Nanjing Jiangsu 210042 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"X.","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Dermatology Chinese Academy of Medical Sciences St 12 Jiangwangmiao Nanjing Jiangsu 210042 China"},{"name":"Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs St 12 Jiangwangmiao Nanjing Jiangsu 210042 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H.","family":"Xu","sequence":"additional","affiliation":[{"name":"Institute of Dermatology Chinese Academy of Medical Sciences St 12 Jiangwangmiao Nanjing Jiangsu 210042 China"},{"name":"Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs St 12 Jiangwangmiao Nanjing Jiangsu 210042 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B.","family":"Wang","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs St 12 Jiangwangmiao Nanjing Jiangsu 210042 China"},{"name":"Institute of Plastic Surgery Chinese Academy of Medical Sciences St 33 Ba-Da-Chu Road Beijing 100144 China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2016,3,1]]},"reference":[{"key":"2023033115534578600_","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1111\/j.1365-2133.2011.10372.x","article-title":"Two novel mutations of the nicastrin gene in Chinese patients with acne inversa","volume":"165","author":"Li","year":"2011","journal-title":"Br J Dermatol"},{"key":"2023033115534578600_","doi-asserted-by":"crossref","first-page":"2459","DOI":"10.1038\/jid.2012.162","article-title":"Mutations in the gamma-secretase genes NCSTN, PSENEN, and PSEN1 underlie rare forms of hidradenitis suppurativa (acne inversa)","volume":"132","author":"Pink","year":"2012","journal-title":"J Invest Dermatol"},{"key":"2023033115534578600_","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.1111\/j.1468-3083.2012.04627.x","article-title":"Two novel mutations of the NCSTN gene in Chinese familial acne inverse","volume":"27","author":"Zhang","year":"2013","journal-title":"J Eur Acad Dermatol Venereol"},{"key":"2023033115534578600_","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1126\/science.1196284","article-title":"Gamma-secretase gene mutations in familial acne inversa","volume":"330","author":"Wang","year":"2010","journal-title":"Science"},{"key":"2023033115534578600_","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.jdermsci.2014.01.013","article-title":"A novel NCSTN mutation alone may be insufficient for the development of familial hidradenitis suppurativa","volume":"74","author":"Nomura","year":"2014","journal-title":"J Dermatol Sci"},{"key":"2023033115534578600_","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1038\/jid.2014.399","article-title":"Acne inversa caused by missense mutations in NCSTN is not fully compatible with impairments in Notch signaling","volume":"135","author":"Zhang","year":"2015","journal-title":"J Invest Dermatol"},{"key":"2023033115534578600_","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1001\/jamadermatol.2014.5306","article-title":"\u03b3-Secretase mutation in an African American family with hidradenitis suppurativa","volume":"151","author":"Chen","year":"2015","journal-title":"JAMA Dermatol"},{"key":"2023033115534578600_","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1016\/j.cell.2005.05.022","article-title":"Nicastrin functions as a gamma-secretase-substrate receptor","volume":"122","author":"Shah","year":"2005","journal-title":"Cell"},{"key":"2023033115534578600_","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1038\/jid.2012.372","article-title":"\u03b3-Secretase mutations in hidradenitis suppurativa: new insights into disease pathogenesis","volume":"133","author":"Pink","year":"2013","journal-title":"J Invest Dermatol"},{"key":"2023033115534578600_","doi-asserted-by":"crossref","first-page":"32264","DOI":"10.1074\/jbc.M703649200","article-title":"Epidermal growth factor receptor and Notch pathways participate in the tumor suppressor function of \u03b3-secretase","volume":"282","author":"Li","year":"2007","journal-title":"J Biol Chem"},{"key":"2023033115534578600_","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.ceb.2008.01.010","article-title":"Epidermal Notch signalling: differentiation, cancer and adhesion","volume":"20","author":"Watt","year":"2008","journal-title":"Curr Opin Cell Biol"},{"key":"2023033115534578600_","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1016\/j.devcel.2004.09.014","article-title":"\u03b3-Secretase functions through Notch signaling to maintain skin appendages but is not required for their patterning or initial morphogenesis","volume":"7","author":"Pan","year":"2004","journal-title":"Dev Cell"},{"key":"2023033115534578600_","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1111\/exd.12098","article-title":"Impaired Notch-MKP-1 signalling in hidradenitis suppurativa: an approach to pathogenesis by evidence from translational biology","volume":"22","author":"Melnik","year":"2013","journal-title":"Exp Dermatol"},{"key":"2023033115534578600_","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1111\/bjd.12068","article-title":"Impaired Notch signalling: the unifying mechanism explaining the pathogenesis of hidradenitis suppurativa (acne inversa)","volume":"168","author":"Melnik","year":"2013","journal-title":"Br J Dermatol"},{"key":"2023033115534578600_","doi-asserted-by":"crossref","first-page":"1506","DOI":"10.1038\/jid.2012.472","article-title":"Identification of three hidradenitis suppurativa phenotypes: latent class analysis of a cross-sectional study","volume":"133","author":"Canoui-Poitrine","year":"2013","journal-title":"J Invest Dermatol"},{"key":"2023033115534578600_","doi-asserted-by":"crossref","first-page":"13349","DOI":"10.1073\/pnas.1414837111","article-title":"Crystal structure of the gamma-secretase component nicastrin","volume":"111","author":"Xie","year":"2014","journal-title":"Proc Natl Acad Sci USA"},{"key":"2023033115534578600_","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1046\/j.1471-4159.2003.02298.x","article-title":"Co-expressed presenilin 1 NTF and CTF form functional gamma-secretase complexes in cells devoid of full-length protein","volume":"89","author":"Laudon","year":"2004","journal-title":"J Neurochem"},{"key":"2023033115534578600_","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.str.2013.09.018","article-title":"Structural interactions between inhibitor and substrate docking sites give insight into mechanisms of human PS1 complexes","volume":"22","author":"Li","year":"2014","journal-title":"Structure"},{"key":"2023033115534578600_","doi-asserted-by":"crossref","first-page":"1631","DOI":"10.1007\/s00018-009-8668-7","article-title":"The Notch signaling pathway: transcriptional regulation at Notch target genes","volume":"66","author":"Borggrefe","year":"2009","journal-title":"Cell Mol Life Sci"},{"key":"2023033115534578600_","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/978-1-4614-0899-4_1","article-title":"The molecular basis of Notch signaling: a brief overview","volume":"727","author":"Kwon","year":"2012","journal-title":"Adv Exp Med Biol"},{"key":"2023033115534578600_","doi-asserted-by":"crossref","first-page":"4583","DOI":"10.1093\/nar\/gkm477","article-title":"Delta-Notch \u2013 and then? Protein interactions and proposed modes of repression by Hes and Hey bHLH factors","volume":"35","author":"Fischer","year":"2007","journal-title":"Nucleic Acids Res"},{"key":"2023033115534578600_","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/S0960-9822(03)00081-2","article-title":"Notch\/RBP-J signaling regulates epidermis\/hair fate determination of hair follicular stem cells","volume":"13","author":"Yamamoto","year":"2003","journal-title":"Curr Biol"},{"key":"2023033115534578600_","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1111\/j.1365-2133.2010.10034.x","article-title":"Hidradenitis suppurativa\/acne inversa: bilocated epithelial hyperplasia with very different sequelae","volume":"164","author":"von Laffert","year":"2011","journal-title":"Br J Dermatol"},{"key":"2023033115534578600_","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1038\/ng1099","article-title":"Notch1 functions as a tumor suppressor in mouse skin","volume":"33","author":"Nicolas","year":"2003","journal-title":"Nat Genet"},{"key":"2023033115534578600_","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1159\/000269836","article-title":"Clinicopathological study of 13 cases of squamous cell carcinoma complicating hidradenitis suppurativa","volume":"220","author":"Lavogiez","year":"2010","journal-title":"Dermatology"},{"key":"2023033115534578600_","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1038\/nrm1619","article-title":"The cornified envelope: a model of cell death in the skin","volume":"6","author":"Candi","year":"2005","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2023033115534578600_","doi-asserted-by":"crossref","first-page":"4882","DOI":"10.1038\/sj.onc.1210274","article-title":"Akt activation induces epidermal hyperplasia and proliferation of epidermal progenitors","volume":"26","author":"Murayama","year":"2007","journal-title":"Oncogene"},{"key":"2023033115534578600_","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1016\/j.oraloncology.2006.08.003","article-title":"Areca nut extract treatment down-regulates involucrin in normal human oral keratinocyte through P13K\/AKT activation","volume":"43","author":"Tseng","year":"2007","journal-title":"Oral Oncol"},{"key":"2023033115534578600_","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/1471-2121-7-10","article-title":"Cellular Notch responsiveness is defined by phosphoinositide 3-kinase-dependent signals","volume":"7","author":"McKenzie","year":"2006","journal-title":"BMC Cell Biol"},{"key":"2023033115534578600_","doi-asserted-by":"crossref","first-page":"5015","DOI":"10.1158\/0008-5472.CAN-08-3478","article-title":"Notch activation induces Akt signaling via an autocrine loop to prevent apoptosis in breast epithelial cells","volume":"69","author":"Meurette","year":"2009","journal-title":"Cancer Res"},{"key":"2023033115534578600_","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1038\/nm.3259","article-title":"Inhibition of Notch uncouples Akt activation from hepatic lipid accumulation by decreasing mTorc1 stability","volume":"19","author":"Pajvani","year":"2013","journal-title":"Nat Med"},{"key":"2023033115534578600_","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1111\/exd.12648","article-title":"Phenotypic heterogeneity implies heterogeneous pathogenic pathways in hidradenitis suppurativa","volume":"24","author":"Frew","year":"2015","journal-title":"Exp Dermatol"},{"key":"2023033115534578600_","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1111\/bjd.12192","article-title":"Predicting response to anti-TNF-\u03b1 treatment in hidradenitis suppurativa","volume":"168","author":"Jemec","year":"2013","journal-title":"Br J Dermatol"},{"issue":"Database issue","key":"2023033115534578600_","doi-asserted-by":"crossref","first-page":"D199","DOI":"10.1093\/nar\/gkt1076","article-title":"Data, information, knowledge and principle: back to metabolism in KEGG","volume":"42","author":"Kanehisa","year":"2014","journal-title":"Nucleic Acids Res"},{"key":"2023033115534578600_","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG: Kyoto encyclopedia of genes and genomes","volume":"28","author":"Kanehisa","year":"2000","journal-title":"Nucleic Acids Res"}],"container-title":["British Journal of Dermatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fbjd.14223","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/bjd\/article-pdf\/174\/3\/522\/49716563\/bjd0522.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bjd\/article-pdf\/174\/3\/522\/49716563\/bjd0522.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,15]],"date-time":"2023-08-15T08:17:33Z","timestamp":1692087453000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bjd\/article\/174\/3\/522\/6617160"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,3,1]]},"references-count":35,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2016,3,1]]},"published-print":{"date-parts":[[2016,3,1]]}},"URL":"https:\/\/doi.org\/10.1111\/bjd.14223","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.725853850.793534533","asserted-by":"object"}]},"ISSN":["1365-2133","0007-0963"],"issn-type":[{"value":"1365-2133","type":"electronic"},{"value":"0007-0963","type":"print"}],"subject":[],"published-other":{"date-parts":[[2016,3,1]]},"published":{"date-parts":[[2016,3,1]]}}}