{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T12:56:45Z","timestamp":1791291405390,"version":"4.3.0"},"reference-count":67,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2003,6,3]],"date-time":"2003-06-03T00:00:00Z","timestamp":1054598400000},"content-version":"vor","delay-in-days":2,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatism"],"published-print":{"date-parts":[[2003,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Transforming growth factor \u03b2 receptors (TGF\u03b2Rs) are known to be expressed at high levels in several fibrotic diseases, including systemic sclerosis. In the present study, we investigated the mechanism of up\u2010regulation of TGF\u03b2R expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The levels of expression of TGF\u03b2R type II (TGF\u03b2RII) messenger RNA (mRNA), with or without stimulation by epidermal growth factor (EGF), were evaluated by Northern blot analysis, and the protein levels were determined by immunoblotting. The transcription activity of the TGF\u03b2RII gene was examined with luciferase assays using the \u22121670\/+35 TGF\u03b2RII promoter luciferase construct.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>EGF up\u2010regulates the expression of TGF\u03b2RII mRNA and protein in human dermal fibroblasts. Actinomycin D, an RNA synthesis inhibitor, significantly blocked the EGF\u2010mediated up\u2010regulation of TGF\u03b2RII mRNA expression, whereas cycloheximide, a protein synthesis inhibitor, did not block this up\u2010regulation. In addition, EGF treatment did not significantly affect the TGF\u03b2RII mRNA half\u2010life. EGF\u2010mediated induction of TGF\u03b2RII expression was inhibited by treatment of fibroblasts with the selective phosphoinositide 3\u2010kinase (PI 3\u2010kinase) inhibitors wortmannin or LY294002, and Akt inhibitor also blocked EGF\u2010induced expression of TGF\u03b2RII. In addition, EGF induced TGF\u03b2RII promoter activity, and this induction was significantly blocked by wortmannin, LY294002, or Akt inhibitor. Cotransfection with a dominant\u2010negative mutant of p85 (the regulatory component of PI 3\u2010kinase) or Akt significantly reduced the induction of TGF\u03b2RII promoter activity by EGF. Moreover, a constitutive active form of p110 (a catalytic component of PI 3\u2010kinase) induced TGF\u03b2RII promoter activity. In addition, scleroderma fibroblasts expressed increased levels of TGF\u03b2RII but did not show further up\u2010regulation of TGF\u03b2RII expression by EGF.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These results indicate that EGF\u2010mediated induction of TGF\u03b2RII expression occurs at the transcription level, does not require de novo protein synthesis, and involves the PI 3\u2010kinase\/Akt signaling pathway, and that abnormal activation of EGF\u2010mediated signaling pathways, including PI 3\u2010kinase or Akt, might play a role in the up\u2010regulation of TGF\u03b2RII in scleroderma fibroblasts.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.11029","type":"journal-article","created":{"date-parts":[[2003,6,4]],"date-time":"2003-06-04T10:07:16Z","timestamp":1054721236000},"page":"1652-1666","source":"Crossref","is-referenced-by-count":28,"title":["Epidermal growth factor up\u2010regulates expression of transforming growth factor \u03b2 receptor type II in human dermal fibroblasts by phosphoinositide 3\u2010kinase\/Akt signaling pathway: Resistance to epidermal growth factor stimulation in scleroderma 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