2010 Fiscal Year Final Research Report
Molecular Basis of the nuclear receptor function mediating Inflammation
| Project/Area Number |
20591089
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Endocrinology
|
|---|
| Research Institution | The University of Tokyo |
|---|
Principal Investigator |
KITAGAWA Hirochika The University of Tokyo, 生体調節研究所, 教授 (20345234)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
TAKEYAMA Kenーichi 東京大学, 分子細胞生物学研究所, 講師 (30323570)
TAKADA Ichiro 東京大学, 分子細胞生物学研究所, 助教 (50361655)
|
|---|
| Project Period (FY) |
2008 – 2010
|
| Keywords | グルココルチコイド / 炎症 / Sumo化 |
|---|
| Research Abstract |
Glucocorticoid is clinically successful in attenuating inflammation caused by diverse diseases, and its anti-inflammatory actions via nuclear glucocorticoid receptor (GR) are known to be mediated by transcriptional repression of inflammatory transcription factors like AP-1 and NF-kB. However, the molecular mechanism underlying hormonal transrepression largely remains to be uncovered at the level of chromatin. Here, we report that glucocorticoid-induced sumoylation of c-Jun via GR triggers transcriptional repression of AP-1 through a histone inactivating methylation (H3K27me3) by recruitment of a polycomb (PRC2) complex. Liganded GR serves as an adaptor for Sumo E3 ligase (PIAS1) to sumoylate c-Jun in the AP-1 unit, but not NF-kB. Sumoylated c-Jun induces association with a PRC2 complex, leading to H3K27 methylation by EZH2 and silencing of AP-1 binding sites on pro-inflammatory cytokine gene promoters. Ablation of EZH2 in mice abrogates glucocorticoid-induced transrepression of the cytokine genes that are induced by activated AP-1. Thus, these findings uncover a molecular mechanism of anti-inflammatory glucocorticoid actions for transrepression of AP-1 through repressive chromatin reorganization, and provide a clue for development of desirable GR synthetic ligands.
|
-
-
[Journal Article] TSPY represses the activity of the androgen receptor in androgen-dependent testicular germ cell tumors.2010
Author(s)
Akimoto C., Ueda T., Yamaoka I., Inoue K., Sakari M.,Ohara K., Fujioka T., Nagahara A., Nonomura N., Tsutsumi S., Aburatani H., Miki T., Matsumoto T., Kitagawa H., Kato S.
-
Journal Title
Proc Natl Acad Sci USA. 107(46)
Pages: 19891-6
Peer Reviewed
-
[Journal Article] Double PHD fingers protein DPF2 recognizes acetylated histones and suppresses the function of ERR{alpha} through histone deacetylase 1.2010
Author(s)
Matsuyama R, Takada I, Yokoyama A, Fujiyama-Nakamura S, Tsuji N, Kitagawa H, Fujiki R, Kim M, Kouzu-Fujita M, Yano T, Kato S.
-
Journal Title
J Biol Chem. 285(24)
Pages: 18166-76
Peer Reviewed
-
-
[Journal Article] CDP/Cut is an Osteoblastic Co-activator of the Vitamin D receptor (VDR).2010
Author(s)
Ochiai E., Kitagawa H., Takada I., Fujiyama S., Sawatsubashi S., Kim M., Mezaki Y., Tshuushima Y., Takagi K., Yamaoka K., Kato S., Kamimura T.
-
Journal Title
Bone Miner Res. (in press)
Peer Reviewed
-
[Journal Article] NF-YC functions as a corepressor of agonist-bound mineralocorticoid receptor.2010
Author(s)
Murai-Takeda A, Shibata H, Kurihara I, Kobayashi S, Yokota K, Suda N, Mitsuishi Y, Jo R, Kitagawa H, Kato S, Saruta T, Itoh H.
-
Journal Title
J.Biol.Chem. 285
Pages: 8084-93
Peer Reviewed
-
-
[Journal Article] DNA demethylation in hormone-induced transcriptional derepression.2009
Author(s)
Kim M., Kondo T., Takada I., Youn M., Yamamoto Y., Takahashi S., Matsumoto T., Fujiyama S., Shirode Y., Yamaoka I., Kitagawa H., Takeyama K., Shibuya H., Ohtake F., Kato S.
-
Journal Title
Nature. 461
Pages: 1007-1012
Peer Reviewed
-
[Journal Article] Distinct function of 2 chromatin remodeling complexes that share a common subunit, Williams syndrome transcription factor (WSTF).2009
Author(s)
Yoshimura K., Kitagawa H., Fujiki R., Tanabe M., Takezawa S., Takada I., Yamaoka I., Yonezawa M., Kondo T., Furutani Y., Yagi H., Yoshinaga S., Masuda T., Fukuda T., Yamamoto Y., Ebihara K., Li D.Y., Matsuoka R., Takeuchi J.K., Matsumoto T., Kato S.
-
Journal Title
Proc Natl Acad Sci USA. 106
Pages: 9280-9285
Peer Reviewed
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
