UM
Flavopiridol inhibits TGF-b-stimulated biglycan synthesis by blocking linker region phosphorylation and nuclear translocation of Smad2
Rostam M.A.3; Shajimoon A.6; Kamato D.5; Mitra P.5; Piva T.J.6; Getachew R.6; Cao Y.4; Zheng W.1; Osman N.6; Little P.J.6
2018-04-01
Source PublicationJournal of Pharmacology and Experimental Therapeutics
ISSN15210103 00223565
Volume365Issue:1Pages:156-164
AbstractTransforming growth factor-b (TGF-b) is a pleiotropic growth factor implicated in the development of atherosclerosis for its role in mediating glycosaminoglycan (GAG) chain hyperelongation on the proteoglycan biglycan, a phenomenon that increases the binding of atherogenic lipoproteins in the vessel wall. Phosphorylation of the transcription factor Smad has emerged as a critical step in the signaling pathways that control the synthesis of biglycan, both the core protein and the GAG chains. We have used flavopiridol, a well-known cyclin-dependent kinase inhibitor, to study the role of linker region phosphorylation in the TGF-b-stimulated synthesis of biglycan. We used radiosulfate incorporation and SDS-PAGE to assess proteoglycan synthesis, real-time polymerase chain reaction to assess gene expression, and chromatin immunoprecipitation to assess the binding of Smads to the promoter region of GAG Synthesizing genes. Flavopiridol blocked TGF-b-stimulated synthesis of mRNA for the GAG synthesizing enzymes, and chondroitin 4-sulfotransferase (C4ST-1), chondroitin sulfate synthase-1 (ChSy-1) and TGF-b-mediated proteoglycans synthesis as well as GAG hyperelongation. Flavopiridol blocked TGF-b-stimulated Smad2 phosphorylation at both the serine triplet and the isolated threonine residue in the linker region. The binding of Smad to the promoter region of the C4ST-1 and ChSy-1 genes was stimulated by TGF-b, and this response was blocked by flavopiridol, demonstrating that linker region phosphorylated Smad can pass to the nucleus and positively regulate transcription. These results demonstrate the validity of the kinases, which phosphorylate the Smad linker region as potential therapeutic target(s) for the development of an agent to prevent atherosclerosis.
DOI10.1124/jpet.117.244483
URLView the original
Language英語
Fulltext Access
Citation statistics
Cited Times [WOS]:16   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionUniversity of Macau
Affiliation1.Universidade de Macau
2.Monash University
3.International Islamic University Malaysia
4.Sun Yat-Sen University
5.University of Queensland
6.RMIT University
Recommended Citation
GB/T 7714
Rostam M.A.,Shajimoon A.,Kamato D.,et al. Flavopiridol inhibits TGF-b-stimulated biglycan synthesis by blocking linker region phosphorylation and nuclear translocation of Smad2[J]. Journal of Pharmacology and Experimental Therapeutics,2018,365(1):156-164.
APA Rostam M.A..,Shajimoon A..,Kamato D..,Mitra P..,Piva T.J..,...&Little P.J..(2018).Flavopiridol inhibits TGF-b-stimulated biglycan synthesis by blocking linker region phosphorylation and nuclear translocation of Smad2.Journal of Pharmacology and Experimental Therapeutics,365(1),156-164.
MLA Rostam M.A.,et al."Flavopiridol inhibits TGF-b-stimulated biglycan synthesis by blocking linker region phosphorylation and nuclear translocation of Smad2".Journal of Pharmacology and Experimental Therapeutics 365.1(2018):156-164.
Files in This Item:
There are no files associated with this item.
Related Services
Recommend this item
Bookmark
Usage statistics
Export to Endnote
Google Scholar
Similar articles in Google Scholar
[Rostam M.A.]'s Articles
[Shajimoon A.]'s Articles
[Kamato D.]'s Articles
Baidu academic
Similar articles in Baidu academic
[Rostam M.A.]'s Articles
[Shajimoon A.]'s Articles
[Kamato D.]'s Articles
Bing Scholar
Similar articles in Bing Scholar
[Rostam M.A.]'s Articles
[Shajimoon A.]'s Articles
[Kamato D.]'s Articles
Terms of Use
No data!
Social Bookmark/Share
All comments (0)
No comment.
 

Items in the repository are protected by copyright, with all rights reserved, unless otherwise indicated.