{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T18:38:40Z","timestamp":1789238320912,"version":"build-2803163510"},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2021,5,1]],"date-time":"2021-05-01T00:00:00Z","timestamp":1619827200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,5,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Asthma is a respiratory disease with a dramatically increasing incidence globally. The present study explored the roles of S-phase kinase-associated protein 2 (SKP2) and forkhead box O3 (FOXO3) in asthma and their involvement in the Kr\u00fcppel-like factor 15\u2013lipoprotein receptor-related protein 5 (KLF15\u2013LRP5) axis. SKP2 expression in patients with asthma and OVA-induced asthmatic Sprague Dawley rats was detected by reverse transcription quantitative PCR and Western blot assays. Alterations in SKP2 and LRP5 expression were evaluated in OVA-induced asthmatic rats, followed by measurement of inflammatory cytokines using ELISA and airway resistance using a methacholine challenge test. We applied TGF-\u03b21 to establish the airway smooth muscle cell (ASMC) proliferation model of asthma. The FOXO3 ubiquitination and changes in cell biological behaviors were detected using immunoprecipitation, MTT, and Annexin V\/propidium iodide assays. Flow cytometry was adopted to detect cell cycle, and ELISA was used to measure the concentrations of IL-4, IL-5, IL-13, and IgE in rat bronchoalveolar lavage fluid. SKP2 was highly expressed and FOXO3 was poorly expressed in patients with asthma and in OVA-induced asthmatic rats. SKP2 silencing decreased IL-4, IL-5, IL-13, and IgE expression in rat bronchoalveolar lavage fluid, whereas SKP2 enhanced FOXO3 ubiquitination to upregulate KLF15, which bound to the LRP5 promoter in TGF-\u03b21\u2013induced ASMCs and increased LRP5 expression. SKP2 enhanced airway hyperresponsiveness and inflammation in the OVA-induced rat model and augmented TGF-\u03b21\u2013induced ASMC proliferation by inhibiting the FOXO3\/KLF15\/LRP5 axis. Additionally, overexpressed SKP2 resulted in reduced numbers of ASMCs in the G1 phase but increased numbers in the G2\/M phase. Collectively, we show that SKP2 promotes FOXO3 ubiquitination to suppress the KLF15-LRP5 axis, thereby exacerbating asthma.<\/jats:p>","DOI":"10.4049\/jimmunol.2000387","type":"journal-article","created":{"date-parts":[[2021,4,9]],"date-time":"2021-04-09T11:00:19Z","timestamp":1617966019000},"page":"2366-2375","source":"Crossref","is-referenced-by-count":15,"title":["SKP2-Promoted Ubiquitination of FOXO3 Promotes the Development of Asthma"],"prefix":"10.1093","volume":"206","author":[{"given":"Bing","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Linyi People\u2019s Hospital , Linyi 276000 ,","place":["People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junxia","family":"Wang","sequence":"additional","affiliation":[{"name":"The First Ward, Department of Pediatrics, Huantai People's Hospital , Zibo 256400 ,","place":["People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhijuan","family":"Ren","sequence":"additional","affiliation":[{"name":"The 6th Department of Pediatrics, Linyi People\u2019s Hospital , Linyi 276000 ,","place":["People\u2019s Republic of China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,5,15]]},"reference":[{"key":"2025030417503187300_r1","doi-asserted-by":"crossref","first-page":"L191","DOI":"10.1152\/ajplung.00138.2013","article-title":"Serotonin 5-HT2 receptor activation prevents allergic asthma in a mouse model","volume":"308","author":"Nau","year":"2015","journal-title":"Am. 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