Transcriptional activation of p21 by Tranilast is mediated via transforming growth factor beta signal pathway.
Tranilast, an antiallergic medication, is a very promising inhibitor of restenosis after balloon angioplasty. Tranilast can prevent the proliferation and migration of smooth muscle cells by activating the gene expression of p21, a strong cyclin/cyclin-dependent kinase (CDK) inhibitor, and by arresting cell growth at the G0/G1 phase. The signaling pathway of Tranilast in regulating p21 is to our best interest and is elucidated in the present study. The major emphasis was weighted on exploring the regulatory effects of Tranilast on promoter activity of p21. By serial deletion analysis, the sequence between -74 and -83 bp of the p21 promoter, previously identified as the transforming growth factor-beta (TGF-beta)-response element, was found sufficient, where as most of the promoter region 5' to -111 bp was found unnecessary for the transcriptional activation of p21 by both TGF-beta1 and Tranilast. Tranilast was also found to induce phosphorylation of Smad2 (a cytoplasmic signaling molecule essential for mediating TGF-beta signal transduction). Transfection of DeltakTbetaRII, a truncated form of TGF-beta type II receptor known to exert a dominant-negative effect on TGF-beta signaling, was found to suppress the signaling of both Tranilast and TGF-beta1 to a similar extent. These results suggested that induction of p21 by Tranilast might be closely related to TGF-beta signal transduction pathway.
Charng
Min-Ji
MJ
Division of Cardiology, Taipei Veterans General Hospital, Taipei, Taiwan.
Wu
Chieh-Hsi
CH
D018926:Anti-Allergic Agents / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000502:physiology*; D062367:ortho-Aminobenzoates / Q000494:pharmacology*; D020741:rho GTP-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*
D018926:Anti-Allergic Agents; D016212:Transforming Growth Factor beta; D062367:ortho-Aminobenzoates; D020741:rho GTP-Binding Proteins; C012293:tranilast