{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T23:14:40Z","timestamp":1772147680999,"version":"3.50.1"},"reference-count":25,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2013,9,1]],"date-time":"2013-09-01T00:00:00Z","timestamp":1377993600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal of Periodontology"],"published-print":{"date-parts":[[2013,9]]},"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Hypoxia\u2010inducible factor\u20101\u03b1 (HIF\u20101\u03b1), the \u03b1 subunit of the heterodimeric transcription factor HIF\u20101, maintains oxygen homeostasis by regulating gene expression. Under normoxic conditions, HIF\u20101\u03b1 expression is maintained at low steady\u2010state levels by the critical oxygen sensor prolyl hydroxylase 2 (PHD2). Transforming growth factor \u03b21 (TGF\u2010\u03b21) activates Smad3 signaling and contributes to HIF\u20101\u03b1 stabilization under normoxic conditions. In chronic periodontitis, HIF\u20101\u03b1 is expressed highly in gingival fibroblasts and upregulates inflammatory factor transcription, which promotes periodontal inflammation. Here, the authors investigated the effect of TGF\u2010\u03b21\/Smad3 signaling and its blockade by the specific inhibitor of Smad3 (SIS3) on HIF\u20101\u03b1 expression and stability in human periodontal ligament cells.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> The authors investigated the effect of TGF\u2010\u03b21 on HIF\u20101\u03b1 protein stability using cycloheximide. Furthermore, they analyzed HIF\u20101\u03b1 expression, PHD2 expression, and Smad3 phosphorylation following TGF\u2010\u03b21 stimulation in the presence or absence of SIS3.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> The half\u2010life of HIF\u20101\u03b1 was prolonged in TGF\u2010\u03b21\u2013treated cells. TGF\u2010\u03b21 treatment induced HIF\u20101\u03b1 gene expression and enhanced HIF\u20101\u03b1 protein stability while decreasing PHD2 expression and activating Smad3 phosphorylation. Notably, HIF\u20101\u03b1 protein expression was not detectable prior to TGF\u2010\u03b21 stimulation. Furthermore, SIS3 treatment abrogated Smad3 phosphorylation, impaired TGF\u2010\u03b21\u2013induced HIF\u20101\u03b1 gene expression and protein stability, and stimulated TGF\u2010\u03b21\u2013mediated PHD2 inhibition.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> These results demonstrate that HIF\u20101\u03b1 transcription and protein synthesis are controlled by TGF\u2010\u03b21\/Smad3 signaling, whereas HIF\u20101\u03b1 protein stability is controlled by PHD2, which is regulated by TGF\u2010\u03b21\/Smad3 signaling.<\/jats:p>","DOI":"10.1902\/jop.2012.120373","type":"journal-article","created":{"date-parts":[[2012,10,22]],"date-time":"2012-10-22T17:24:20Z","timestamp":1350926660000},"page":"1346-1352","source":"Crossref","is-referenced-by-count":22,"title":["Inhibition of Transforming Growth Factor \u03b21\/Smad3 Signaling Decreases Hypoxia\u2010Inducible Factor\u20101\u03b1 Protein Stability by Inducing Prolyl Hydroxylase 2 Expression in Human Periodontal Ligament Cells"],"prefix":"10.1002","volume":"84","author":[{"given":"Teppei","family":"Watanabe","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akihiro","family":"Yasue","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eiji","family":"Tanaka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2013,9]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.12.5510"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0955-0674(00)00194-0"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1366"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00507-4"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/cdg392"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.42.2.659-667.1983"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.4161\/cc.4.2.1407"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1902\/jop.1984.55.9.516"},{"issue":"5","key":"e_1_2_7_10_1","first-page":"450","article-title":"Role of transforming growth factor beta in the pathophysiology of chronic inflammation","volume":"64","author":"Wahl SM","year":"1993","journal-title":"J Periodontol"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1161\/hh1301.092678"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1902\/jop.2010.100100"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1902\/jop.1993.64.5s.474"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0065-2776(00)75003-6"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/16.17.5353"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.105.017483"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M403057200"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1999.17.2.607"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-1096-03"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.20067"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20041736"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M604507200"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.00-0732fje"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.1041540308"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj3500307"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/ken086"}],"container-title":["Journal of Periodontology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/aap.onlinelibrary.wiley.com\/doi\/pdf\/10.1902\/jop.2012.120373","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,19]],"date-time":"2025-10-19T12:52:53Z","timestamp":1760878373000},"score":1,"resource":{"primary":{"URL":"https:\/\/aap.onlinelibrary.wiley.com\/doi\/10.1902\/jop.2012.120373"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,9]]},"references-count":25,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2013,9]]}},"alternative-id":["10.1902\/jop.2012.120373"],"URL":"https:\/\/doi.org\/10.1902\/jop.2012.120373","archive":["Portico"],"relation":{},"ISSN":["0022-3492","1943-3670"],"issn-type":[{"value":"0022-3492","type":"print"},{"value":"1943-3670","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,9]]}}}