Flavopiridol Inhibits TGF-β-Stimulated Biglycan Synthesis by Blocking Linker Region Phosphorylation and Nuclear Translocation of Smad2

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	Flavopiridol Inhibits TGF-β-Stimulated Biglycan Synthesis by Blocking Linker Region Phosphorylation and Nuclear Translocation of Smad2
	Muhamad A. Rostam; Aravindra Shajimoon; Danielle Kamato; Partha Mitra; Terrence J. Piva; Robel Getachew; Yingnan Cao; Wenhua Zheng; Narin Osman; Peter J. Little
	2018-04-01
Source Publication	Journal of pharmacology and experimental therapeutics
ISSN	0022-3565
Pages	156-164
Abstract	Transforming growth factor-β (TGF-β) 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-β-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-β-stimulated synthesis of mRNA for the GAG synthesizing enzymes, and chondroitin 4-sulfotransferase (C4ST-1), chondroitin sulfate synthase-1 (ChSy-1) and TGF-β-mediated proteoglycans synthesis as well as GAG hyperelongation. Flavopiridol blocked TGF-β-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-β, 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.
Keyword	Flavopiridol Tgf-β
URL	View the original
Indexed By	SCIE
Language	英語English
The Source to Article	PB_Publication
Document Type	Journal article
Collection	University of Macau
Recommended Citation GB/T 7714	Muhamad A. Rostam,Aravindra Shajimoon,Danielle Kamato,et al. Flavopiridol Inhibits TGF-β-Stimulated Biglycan Synthesis by Blocking Linker Region Phosphorylation and Nuclear Translocation of Smad2[J]. Journal of pharmacology and experimental therapeutics, 2018, 156-164.
APA	Muhamad A. Rostam., Aravindra Shajimoon., Danielle Kamato., Partha Mitra., Terrence J. Piva., Robel Getachew., Yingnan Cao., Wenhua Zheng., Narin Osman., & Peter J. Little (2018). Flavopiridol Inhibits TGF-β-Stimulated Biglycan Synthesis by Blocking Linker Region Phosphorylation and Nuclear Translocation of Smad2. Journal of pharmacology and experimental therapeutics, 156-164.
MLA	Muhamad A. Rostam,et al."Flavopiridol Inhibits TGF-β-Stimulated Biglycan Synthesis by Blocking Linker Region Phosphorylation and Nuclear Translocation of Smad2".Journal of pharmacology and experimental therapeutics (2018):156-164.

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