Transcriptional control by mediators and their physiological significance

介质的转录控制及其生理意义

• 批准号: 14002011
• 负责人: ISHII Shunsuke
• 金额: $ 380.22万
• 依托单位: The Institute of Physical and Chemical Research
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Specially Promoted Research
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-14002011/
• 关键词: Gene expression; Transcription control; Transcription mediators; Transcription factors; Development; Mice; Drosophila; Structure

To understand the mediator-dependent transcriptional control, the following 4 aspects of research were performed.1) Switching between coactivators and corepressrs on the transcription factor: We found that transcription factor c-Myb competitively binds to the cocativator CBP and to multiple corespressors, including Ski.Further, p53 binds to and recruit corepressor mSin3A to c-Myb. leading to repression of transcription of the cell-cycle regulator genes.2) Regulation of mediators by specific signaling: We demonstrated that Wnt signal activates the HIPK2 kinase, which acts as a corepressor, and leads to binding of NLK kinase to c-Myb. NLK directly phosphorylates c-Myb and its proteasome-dependent degradation. In the case of A-Myb, HIPK2 recruites histome methyltransferase to A-Myb, but does not induce the A-Myb degradation.3) Physiological role of mediators : By analysis of Ski knockout mice, we found that Ski acts as a corepressor of Gli3, which functions in the hedgehog signaing pathway. We also found that the Shn-2 knockout mice have the defective adipocyte differentiation. Shn-2 acts as a platform protein and mediates the interaction between coactivators and multiple transcription factors to synergistically induce transcription of the PPAR□2 gene, which is essential for the adipocyte differentiation.4) Analysis of the nuclear architecture in transcriptional control : We identified the factor that regulates the subnuclear localization of transcription factors, which play an important role in development.

为了了解介导依赖性转录控制，进行了以下4个方面的研究。1）转录因子上的共激活子和辅阻遏物之间的切换：我们发现转录因子c-Myb竞争性地与共激活子CBP和多个辅阻遏物（包括Ski）结合。此外，p53与辅阻遏物mSin3A结合并将辅阻遏物mSin3A招募到c-Myb。导致细胞周期调节基因转录的抑制。2）通过特定信号传导调节介质：我们证明Wnt信号激活HIPK2激酶，HIPK2激酶充当辅阻遏物，并导致NLK激酶与c-Myb结合。 NLK 直接磷酸化 c-Myb 及其蛋白酶体依赖性降解。在A-Myb的情况下，HIPK2将组织组甲基转移酶募集到A-Myb，但不诱导A-Myb降解。3）介质的生理作用：通过对Ski敲除小鼠的分析，我们发现Ski充当Gli3的辅阻遏物，Gli3在刺猬信号通路中发挥作用。我们还发现Shn-2基因敲除小鼠的脂肪细胞分化有缺陷。 Shn-2作为平台蛋白，介导共激活子和多个转录因子之间的相互作用，协同诱导PPAR□2基因的转录，这对于脂肪细胞的分化至关重要。4）转录控制中的核结构分析：我们鉴定了调节转录因子亚核定位的因子，其在发育中发挥重要作用。

项目成果

Regulation of T helper type 2 cell differentiation by murine Schnurri-2.

• DOI: 10.1084/jem.20040733
• 发表时间: 2005-02-07
• 期刊: JOURNAL OF EXPERIMENTAL MEDICINE
• 影响因子: 15.3
• 作者: Kimura, MY;Hosokawa, H;Yamashita, M;Hasegawa, A;Iwamura, C;Watarai, H;Taniguchi, M;Takagi, T;Ishii, S;Nakayama, T
• 通讯作者: Nakayama, T

Dai, P.et al.: "A Hedgehog-responsive region in the Drosophila wing disc is defined by debra-mediated ubiquitination and lysosomal degradation of Ci."Developmental Cell. 4. 917-928 (2003)

Dai, P. 等人：“果蝇翼盘中的刺猬响应区域是由 debra 介导的 Ci 泛素化和溶酶体降解定义的。”发育细胞。

Schnurri-2 controls memory Th1 and Th2 cell numbers in vivo

• DOI: 10.4049/jimmunol.178.8.4926
• 发表时间: 2007-04-15
• 期刊: JOURNAL OF IMMUNOLOGY
• 影响因子: 4.4
• 作者: Kimura, Motoko Y.;Iwamura, Chiaki;Nakayama, Toshinori
• 通讯作者: Nakayama, Toshinori

SKI activates Wnt/beta-catenin signaling in human melanoma.

• 发表时间: 2003
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Dahu Chen;Wei-dong Xu;E. Bales;C. Colmenares;Maralice Conacci-Sorrell;S. Ishii;E. Stavnezer;J. Campisi;D. Fisher;A. Ben-Ze'ev;E. Medrano

The Wnt-NLK signaling pathway inhibits A-Myb activity by inhibiting the association with coactivator CBP and methylating histone H3

• DOI: 10.1091/mbc.e05-05-0470
• 发表时间: 2005-10-01
• 期刊: MOLECULAR BIOLOGY OF THE CELL
• 影响因子: 3.3
• 作者: Kurahashi, T;Nomura, T;Ishii, S
• 通讯作者: Ishii, S