https://scholars.lib.ntu.edu.tw/handle/123456789/188214
標題: | 血小板衍生生長因子促進腎膈細胞細胞週期的訊息傳導機轉 | 其他標題: | Pentoxifylline Inhibits Platelet-Derived Growth Factor-Stimulated Cyclin D1 Expression in Mesangial Cells by Blocking Akt Membrane Translocation | 作者: | 林水龍 | 公開日期: | 2003 | 出版社: | 臺北市:國立臺灣大學醫學院內科 | 起(迄)頁: | 811-822 | 來源出版物: | MOLECULAR PHARMACOLOGY 64 | 摘要: | Pentoxifylline (PTX) is a potent inhibitor of mesangial cell pro-liferation, but its underlying mechanism is poorly understood. Here, we demonstrate that in platelet-derived growth factor (PDGF)-stimulated mesangial cells, PTX causes G1 arrest by down-regulation of cyclin D1 expression, which subsequently attenuates Cdk4 activity. In vivo, PTX similarly reduces cyclin D1 expression in mesangial cells of rats with acute Thy1 glo-merulonephritis. The mechanism by which PTX reduces cyclin D1 is also investigated. PTX blocks Akt but not phosphatidyl-inositol 3-kinase (PI3K) activation in response to PDGF and abrogates cyclin D1 induction by PI3K, suggesting an effect of PTX on Akt itself. Indeed, PTX is capable of blocking the membrane translocation of Akt, and enforced targeting of Akt to cell membrane prevents the inhibition of Akt and cyclin D1 by PTX. Because PTX is known to increase intracellular cAMP levels by inhibiting phosphodiesterase, the role of protein ki-nase A (PKA) in these events is investigated. The PKA antago-nist N-[2-(4-bromocinnamylamino)ethyl]-5-isoquinoline (H89) abolishes cell proliferation effects of PTX and restores cyclin D1 expression as well as Akt membrane translocation and activa-tion by PDGF, whereas dibutyryl cAMP and forskolin recapitu-late the functions of PTX in mesangial cells. In conclusion, our results indicate that PTX, acting through PKA, interferes with PDGF signaling to Akt activation by blocking Akt membrane translocation, thereby inhibiting cyclin D1 expression and mes-angial cell proliferation. |
URI: | http://ntur.lib.ntu.edu.tw//handle/246246/23613 | 其他識別: | 912314B002347 | Rights: | 國立臺灣大學醫學院內科 |
顯示於: | 醫學系 |
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912314B002347.pdf | 751.8 kB | Adobe PDF | 檢視/開啟 |
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