Molecular regulatory mechanism of suppressor of cytokine signaling (SOCS) in TLR signaling

TLR信号传导中细胞因子信号传导抑制因子(SOCS)的分子调控机制

• 批准号: 17390488
• 负责人: HANAZAWA Shigemasa
• 金额: $ 9.66万
• 依托单位: Nihon University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17390488/
• 关键词: TLR; SOCS; Regulatory molecule; Interacting protein; Regulatory mechanisms

We screened proteins that interact with human suppressor of cytokine signalin-3(hSOCS-3) from a human testis cDNA library, using yeast-two hybrid system. And we found that DP-1, an important regulatory factor during cell cycling, is detected as a its interacting protein with high ratio. A recent study has suggested that Toll-like receptor (TLR) 4 signaling is able to stimulate cell proliferation of human fibroblasts. This study proposed to us a possible mechanism that DP-1 acts as a regulatory factor of TLR -mediated stimulation of the cell proliferation. Thus, in this study, we investigated with detail a molecular mechanism between hSOCS-3 and DP-1 and also explored a novel regulatory action of SOCS-3 in TLR 4 signaling system. And we observed N terminal 156-172 region of hSOCS-3 is a domain that is able to interact with DP-1. This defected mutant of hSOCS-3 was not able to inhibit cycline E-dependent transcriptional activity in HEK 293 cells. Our cytoflow analysis exhibited that wild hSOCS-3 significantly retarded DP-1-mediated cell cycle and proliferation of HEK 292 cells. However, such retardation was not observed in the cells transfected with defected mutant of hSOCS-3. These results demonstrated that hSOCS-3 is an important regulatory molecule in DP-1-dependent cell cycling system and also proposed to us a possibility that h-SOCS-3 may act as a potent regulator of TLR-mediated cell proliferation via DP-1.

我们使用酵母 - 两种混合系统筛选了与人类睾丸cDNA库的细胞因子信号3（HSOCS-3）相互作用的蛋白质。我们发现DP-1是细胞循环过程中的重要调节因子，被检测为具有高比例的相互作用蛋白。最近的一项研究表明，Toll样受体（TLR）4信号传导能够刺激人成纤维细胞的细胞增殖。这项研究向我们提出了一种可能的机制，即DP -1充当TLR介导的细胞增殖刺激的调节因素。因此，在这项研究中，我们详细研究了HSOCS-3和DP-1之间的分子机制，并探讨了SOCS-3在TLR 4信号系统中的新调节作用。我们观察到HSOCS-3的N端子156-172区域是能够与DP-1相互作用的域。该缺陷的HSOCS-3突变体无法抑制HEK 293细胞中的环素E依赖性转录活性。我们的Cytoflow分析表明，野生HSOCS-3显着阻碍DP-1介导的细胞周期和HEK 292细胞的增殖。然而，在用缺陷的HSOCS-3突变体转染的细胞中观察到这种迟缓。这些结果表明，HSOCS-3是DP-1依赖性细胞循环系统中重要的调节分子，并且还向我们提出了H-SOCS-3可以通过DP-1充当TLR介导的细胞增殖的有效调节剂。

项目成果

Identification and characteri- zation of novel isoforms of human DP-1: DP-1{alpha} regulates the transcriptional activity of E2F1 as well as cell cycle progression in a dominant-negative manner.

人类 DP-1 新亚型的鉴定和表征：DP-1{alpha} 以显性失活方式调节 E2F1 的转录活性以及细胞周期进程。

• 发表时间: 2005
• 期刊: J.Biol.Chem. 280・26
• 作者: Ishida H;Masuhiro Y;Fukushima A;Argueta JG;Yamaguchi N;Shiota S;Hanazawa S.
• 通讯作者: Hanazawa S.

Splicing potentiation by growth factor signals via estrogen receptor phosphorylation.

• DOI: 10.1073/pnas.0503197102
• 发表时间: 2005-06
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Y. Masuhiro;Y. Mezaki;Matomo Sakari;K. Takeyama;Tasuku Yoshida;Kunio Inoue;J. Yanagisawa;S. Hanazawa;B. O’Malley;S. Kato

Identification and characterization of novel isoforms of human DP-1:DP-1{alpha} regulates the transcriptional activity of E2F1 as well as cell cycle progression in a dominant-negative manner.

人类 DP-1 新亚型的鉴定和表征：DP-1{α} 以显性失活方式调节 E2F1 的转录活性以及细胞周期进程。

• 发表时间: 2005
• 期刊: J.Biol.Chem. 280(26)
• 作者: Ishida;H.;Masuhiro;Y.;Hanazawa;S.et al.
• 通讯作者: S.et al.

An ortho dimer of butylated hydroxyanisole inhibits nuclear factor kappa B activation and gene expression of inflammatory cytokines in macrophages stimulated by Porphyromonas gingivalis fimbriae

• DOI: 10.1016/j.abb.2006.02.005
• 发表时间: 2006-05-15
• 期刊: ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
• 影响因子: 3.9
• 作者: Murakami, Yukio;Shoji, Masao;Fujisawa, Seiichiro
• 通讯作者: Fujisawa, Seiichiro

Adiponectin inhibits osteoclast formation stimulated by lipopolysaccharide from Actinobacillus actinomycetemcomitans.

• DOI: 10.1111/j.1574-695x.2006.00164.x
• 发表时间: 2007-02
• 期刊: FEMS immunology and medical microbiology
• 作者: N. Yamaguchi;T. Kukita;Yin-Ji Li;Jose Guillermo Martinez Argueta;Toshiyuki Saito;S. Hanazawa;Y. Yamashita