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TGF-beta Regulates the Stability of ...

Coricor, George.

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TGF-beta Regulates the Stability of SOX9 in Cartilage.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	TGF-beta Regulates the Stability of SOX9 in Cartilage./
作者:	Coricor, George.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2017,
面頁冊數:	117 p.
附註:	Source: Dissertation Abstracts International, Volume: 78-10(E), Section: B.
Contained By:	Dissertation Abstracts International78-10B(E).
標題:	Cellular biology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10263326
ISBN:	9781369826258

TGF-beta Regulates the Stability of SOX9 in Cartilage.
Coricor, George.

TGF-beta Regulates the Stability of SOX9 in Cartilage. - Ann Arbor : ProQuest Dissertations & Theses, 2017 - 117 p.

Source: Dissertation Abstracts International, Volume: 78-10(E), Section: B.

Thesis (Ph.D.)--The University of Alabama at Birmingham, 2017.

One out of two people in the U.S. will experience some form of Osteoarthritis (OA) in their lifetime. Members of the Transforming Growth Factor-beta (TGF-beta) superfamily are important factors that stimulate chondrocyte matrix biosynthesis. Mice with a dominant-negative mutation of the TGF-betaIIR develop a degenerative joint disease resembling OA. Another key chondrogenic factor, SOX9, is important for maintaining chondrocyte function. SOX9 and TGF-beta receptors are decreased in OA patients. Our overall hypothesis is that TGF-beta regulates SOX9 to maintain articular cartilage. We utilized two cell culture models for these experiments, ATDC5 cells, and primary bovine articular chondrocytes. We showed that TGF-beta stabilizes SOX9 protein and increases phosphorylation of SOX9 in both ATDC5 and bovine articular chondrocytes. SOX9 can be phosphorylated on three Serine residues S64, S181, and S211. We mutated these serine sites to alanine and found that mutation of Serine 211 is required to maintain normal SOX9 protein levels and that TG-Fbeta was not able to increase the stability of SOX9-S211A mutant. The results suggest that TGF-beta may phosphorylate SOX9 on S211 to stabilize it. The S211 site is in a motif that is targeted by p38 kinase. TGF-beta can signal through a canonical/Smad-mediated pathway or non-conical pathways, including p38. We tested the hypothesis that Smad2/3 and/or p38 regulate the phosphorylation and stability of SOX9. First, we determined that knock down of Smad2/3 using siRNA, blocked TGF-beta-mediated stability of Sox9. Then we showed that stabilization of SOX9 by TGF-beta was blocked in cells treated with p38 inhibitors suggesting that TGF-beta requires both Smad2/3 and p38 activity to regulate SOX9 protein levels. Previously, we showed that Papss2 is a downstream target of TGF-beta. We utilized siRNA for SOX9 to show that TGF-beta requires SOX9 to regulate Papss2. We also showed that p38 is required for TGF-beta-mediated regulation of PAPSS2 suggesting a new mechanism for TGF-beta-mediated gene regulation in chondrocytes. Understanding how TGF-beta stabilizes SOX9 may lead to identification of preventative targets of both age-related and post-traumatic OA.

ISBN: 9781369826258Subjects--Topical Terms:

3172791
Cellular biology.

TGF-beta Regulates the Stability of SOX9 in Cartilage.
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