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The present study analyzed the effect of glucocorticoids on key regulatory pathways leading to passage of cells through the restriction point of the cell cycle, including those mediated by extracellular-regulated kinases (ERK) 1 and 2; the ERK upstream regulator MAPK kinase (MEK1); cyclin D1 levels; and levels and phosphorylation of retinoblastoma protein (pRb). Fluticasone propionate, a new inhaled glucocorticoid, was at least 10-fold more potent than dexamethasone in inhibiting thrombin-stimulated DNA synthesis and increases in cell number. Thrombin-stimulated increases in the levels and hyperphosphorylation of pRb were inhibited by glucocorticoids, which also reduced thrombin-stimulated cyclin D1 protein and messenger RNA (mRNA) levels. PD98059 (10 \u03bcM), an inhibitor of MEK1 activation, markedly attenuated thrombin stimulation of ERK activity and phosphorylation, DNA synthesis, and cyclin D1 levels. However, glucocorticoids had no effect on ERK activity or phosphorylation at 5 min, 2 h, or 12 h after addition of thrombin. In conclusion, glucocorticoid-induced reduction of cyclin D1 mRNA and protein levels, and of pRb phosphorylation, is sufficient to account for inhibition of ASM proliferation. Furthermore, these inhibitory effects of glucocorticoids on cyclin D1 and pRb occur on a component of the mitogen signaling cascade that is either downstream of or parallel to the ERK pathway.<\/jats:p>","DOI":"10.1165\/ajrcmb.21.1.3396","type":"journal-article","created":{"date-parts":[[2013,4,3]],"date-time":"2013-04-03T21:56:28Z","timestamp":1365026188000},"page":"77-88","source":"Crossref","is-referenced-by-count":120,"title":["Glucocorticoids Inhibit Proliferation, Cyclin D1 Expression, and Retinoblastoma Protein Phosphorylation, but Not Activity of the Extracellular-Regulated Kinases in Human Cultured Airway Smooth Muscle"],"prefix":"10.1093","volume":"21","author":[{"given":"Darren","family":"Fernandes","sequence":"first","affiliation":[{"name":"Department of Pharmacology, University at Melbourne; Bernard O'Brien Institute of Microsurgery, St. Vincent's Hospital, Melbourne; and Department of Respiratory Medicine, Alfred Hospital, Melbourne, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Guida","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University at Melbourne; Bernard O'Brien Institute of Microsurgery, St. Vincent's Hospital, Melbourne; and Department of Respiratory Medicine, Alfred Hospital, Melbourne, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Koutsoubos","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University at Melbourne; Bernard O'Brien Institute of Microsurgery, St. Vincent's Hospital, Melbourne; and Department of Respiratory Medicine, Alfred Hospital, Melbourne, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trudi","family":"Harris","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University at Melbourne; Bernard O'Brien Institute of Microsurgery, St. Vincent's Hospital, Melbourne; and Department of Respiratory Medicine, Alfred Hospital, Melbourne, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Vadiveloo","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University at Melbourne; Bernard O'Brien Institute of Microsurgery, St. Vincent's Hospital, Melbourne; and Department of Respiratory Medicine, Alfred Hospital, Melbourne, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John W.","family":"Wilson","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University at Melbourne; Bernard O'Brien Institute of Microsurgery, St. Vincent's Hospital, Melbourne; and Department of Respiratory Medicine, Alfred Hospital, Melbourne, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alastair G.","family":"Stewart","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University at Melbourne; Bernard O'Brien Institute of Microsurgery, St. Vincent's Hospital, Melbourne; and Department of Respiratory Medicine, Alfred Hospital, Melbourne, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[1999,7,1]]},"reference":[{"key":"2026030700091386400_B1","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1136\/thx.24.2.176","article-title":"A comparison of the quantitative anatomy of the bronchi in normal subjects, in status asthmaticus, in chronic bronchitis, and in emphysema.","volume":"24","author":"Dunnill","year":"1969","journal-title":"Thorax"},{"key":"2026030700091386400_B2","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1002\/path.1711010212","article-title":"Hyperplasia of bronchial muscle in chronic bronchitis.","volume":"101","author":"Hossain","year":"1970","journal-title":"J. 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