オカザキ　ケン   Okazaki Ken   岡崎　賢    所属   医学部 医学科（東京女子医科大学病院）    職種   教授・基幹分野長
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	FOXO1 transcription factor regulates chondrogenic differentiation through transforming growth factor β1 signaling.
掲載誌名	正式名：The Journal of biological chemistry 略　 称：J Biol Chem ISSNコード：1083351X/00219258
掲載区分	国外
巻・号・頁	294(46),pp.17555-17569
著者・共著者	Kurakazu Ichiro, Akasaki Yukio, Hayashida Mitsumasa, Tsushima Hidetoshi, Goto Norio, Sueishi Takuya, Toya Masakazu, Kuwahara Masanari, Okazaki Ken, Duffy Tomas, Lotz Martin K, Nakashima Yasuharu
発行年月	2019/11
概要	The forkhead box O (FOXO) proteins are transcription factors involved in the differentiation of many cell types. Type II collagen (Col2) Cre-Foxo1-knockout and Col2-Cre-Foxo1,3,4 triple-knockout mice exhibit growth plate malformation. Moreover, recent studies have reported that in some cells, the expressions and activities of FOXOs are promoted by transforming growth factor β1 (TGFβ1), a growth factor playing a key role in chondrogenic differentiation. Here, using a murine chondrogenic cell line (ATDC5), mouse embryos, and human mesenchymal stem cells, we report the mechanisms by which FOXOs affect chondrogenic differentiation. FOXO1 expression increased along with chondrogenic differentiation, and FOXO1 inhibition suppressed chondrogenic differentiation. TGFβ1/SMAD signaling promoted expression and activity of FOXO1. In ATDC5, FOXO1 knockdown suppressed expression of sex-determining region Y box 9 (Sox9), a master regulator of chondrogenic differentiation, resulting in decreased collagen type II α1 (Col2a1) and aggrecan (Acan) expression after TGFβ1 treatment. On the other hand, chemical FOXO1 inhibition suppressed Col2a1 and Acan expression without suppressing Sox9 To investigate the effects of FOXO1 on chondrogenic differentiation independently of SOX9, we examined FOXO1's effects on the cell cycle. FOXO1 inhibition suppressed expression of p21 and cell-cycle arrest in G0/G1 phase. Conversely, FOXO1 overexpression promoted expression of p21 and cell-cycle arrest. FOXO1 inhibition suppressed expression of nascent p21 RNA by TGFβ1, and FOXO1 bound the p21 promoter. p21 inhibition suppressed expression of Col2a1 and Acan during chondrogenic differentiation. These results suggest that FOXO1 is necessary for not only SOX9 expression, but also cell-cycle arrest during chondrogenic differentiation via TGFβ1 signaling.
DOI	10.1074/jbc.RA119.009409
PMID	31601652