Regulation of endothelial cell activation by TGF-β family signaling

通过 TGF-β 家族信号传导调节内皮细胞活化

• 批准号: 17390073
• 负责人: ITOH Susumu
• 金额: $ 9.28万
• 依托单位: University of Tsukuba
• 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-17390073/
• 关键词: Angiogenesis; TGF-beta; Smad; E2-2; CGI-128; Embryonic lethality; Id1; Herp2; 転写因子; BMP; 胎盤

We have already shown that Id1 and Herp2 promote and block angiogenic responses in endothelial cells, respectively. In present study, we tried to isolate Id1-and Herp2-interacting molecules which modulate function of Id1 and Herp2 by yeast two hybrid method. Among molecules isolated, E2-2, Id2, CGI-128, FHL2 and FLJ13861 could interact with either Id1 or Herp2 in mammalian cells. Out of them, we focused on E2-2 in further experiments because the heterodimer complex formation between E2-2 and Id1 was the strongest. Indeed, Id1 efficiently inhibited E2-2-induced luciferase activity. When E2-2 was over-expressed in endothelial cells, serum-induced proliferation and network formation in endothelial cells was suppressed in contrast with expression of Id1 in endothelial cells. To elucidate the mechanism by which E2-2 blocks angiogenic responses in endothelial cells, we tested the expression of VEGFR2, of which expression is known to be induced during endothelial activation, in endothelial ce … More lls when E2-2 was expressed in cells. As expected, expression of VEGFR2 mRNA was inhibited by E2-2, whereas E2-2-mediated decrease of VEGFR2 expression was improved by introduction of Id1 in the cells. Consistent with reduction of VEGFR2 mRNA, VEGFR2-lucifease activity was blocked by E2-2. Thus, it is possible that Id1 potentiates angiogenic responses in endothelial cells due to making heterodimer with E2-2 which substantially suppresses endothelial cell activation by blocking of VEGFR2 transcript.We also made ALK5 knock-in mice which can not transduce TGF-β/ALK5 signaling, but still possess TGF-β/ALK1 signaling. ALK5 knock-in mice die at E10.5 like ALK5 knock-out mice. We could not observe any mature vessel formation in yolk sac in ALK5 knock-in mice. The phenotype of yolk sac from ALK5 knock-in mice was quite similar to that from ALK5 knock-out mice. However, labyrinth formation in placenta from ALK5 knock-in mice could be detected in contrast with ALK5 knock-out mice. Thus, TGF-β/ALK1 signaling might improve defect of labyrinth formation seen in ALK5 knock-out mice. Less

我们已经证明，Id1和Herp2分别促进和阻断内皮细胞的血管生成反应。在本研究中，我们试图通过酵母双杂交法分离调控Id1和Herp2功能的Id1和Herp2相互作用分子。在分离到的分子中，E2-2、Id2、CGI-128、FHL2和FLJ13861在哺乳动物细胞中都能与Id1或Herp2相互作用。其中，我们在进一步的实验中重点研究了E2-2，因为E2-2和Id1之间的异二聚体复合体的形成是最强烈的。事实上，Id1有效地抑制了E2-2诱导的荧光素酶活性。当E2-2在内皮细胞中过表达时，血清诱导的内皮细胞增殖和网络形成受到抑制，而Id1在内皮细胞中的表达则相反。为了阐明E2-2阻断内皮细胞血管生成反应的机制，我们检测了内皮细胞…中VEGFR2的表达，这种表达是在内皮激活过程中被诱导的E2-2在细胞内表达时，LLS较多。正如预期的那样，VEGFR2的表达被E2-2抑制，而E2-2介导的VEGFR2表达的降低可以通过Id1在细胞中得到改善。与VEGFR2基因表达下调一致，E2-2可阻断VEGFR2-荧光素酶活性。因此，Id1可能通过与E_2形成异二聚体，通过阻断血管内皮生长因子2的转录而显著抑制血管内皮细胞的活化，从而增强血管生成反应。Alk5基因敲除小鼠与Alk5基因敲除小鼠一样，在E10.5死亡。Alk5基因敲除小鼠卵黄囊内未见成熟血管形成。Alk5基因敲除小鼠卵黄囊的表型与Alk5基因敲除小鼠的卵黄囊表型非常相似。然而，与Alk5基因敲除小鼠相比，Alk5基因敲除小鼠的胎盘中可以检测到迷路的形成。因此，转化生长因子β/alk1信号通路可能改善了alk5基因敲除小鼠迷路形成的缺陷。较少

项目成果

ELAC2, a putative prostate cancer susceptibility gene product, potentiates TGF-β/Smad-induced growth arrest of prostate cells

• DOI: 10.1038/sj.onc.1209571
• 发表时间: 2006-09-14
• 期刊: ONCOGENE
• 影响因子: 8
• 作者: Noda, D.;Itoh, S.;Kato, M.
• 通讯作者: Kato, M.

Compensatory mechanisms activated during vasculogenesis in mice by TGFB-receptor deletion.

小鼠血管发生过程中 TGFB 受体缺失激活的补偿机制。

• 期刊: J.Cell.Sci. (revised)
• 作者: Susumu Itoh;Peter ten Dijke;Susumu Itoh;Masako Inamitsu et al.;Daisuke Noda et al.;Gudrun Valdimarsdottir et al.;Masako Inamitsu et al.;Daisuke Noda et al.;Gudrun Valdimarsdottir et al.;Daisuke Noda;Gudrun Valdimarsdottir;Masako Inamnitsu;Daisuke Noda et al.;Rita L.C.Carvalho et al.;Rita L.C.Carvalho et al.
• 通讯作者: Rita L.C.Carvalho et al.

Smad7 and protein phosphatase la are critical determinants in the duration of TGF-β/ALK1 signaling in endothelial cells

Smad7 和蛋白磷酸酶 la 是内皮细胞中 TGF-β/ALK1 信号传导持续时间的关键决定因素

• 发表时间: 2006
• 期刊: BMC Cell.Biol. 7:16
• 作者: Susumu Itoh;Peter ten Dijke;Susumu Itoh;Masako Inamitsu et al.;Daisuke Noda et al.;Gudrun Valdimarsdottir et al.;Masako Inamitsu et al.;Daisuke Noda et al.;Gudrun Valdimarsdottir et al.
• 通讯作者: Gudrun Valdimarsdottir et al.

Smad7 and protein phosphatase 1α are critical determinants in the duration of TGF-β/ALK1 signaling in endothelial cells.

Smad7 和蛋白磷酸酶 1α 是内皮细胞中 TGF-β/ALK1 信号持续时间的关键决定因素。

• 发表时间: 2006
• 期刊: BMC Cell Biol. 7:16
• 作者: Susumu Itoh;Peter ten Dijke;Susumu Itoh;Masako Inamitsu et al.;Daisuke Noda et al.;Gudrun Valdimarsdottir et al.;Masako Inamitsu et al.;Daisuke Noda et al.;Gudrun Valdimarsdottir et al.;Daisuke Noda;Gudrun Valdimarsdottir
• 通讯作者: Gudrun Valdimarsdottir

Compensatory mechanisms activated during vasculogenesis in mice by TGFβ-receptor deletion.

小鼠血管发生过程中 TGFβ 受体缺失激活的补偿机制。

• 期刊: J. Cell Sci (revised)
• 作者: Susumu Itoh;Peter ten Dijke;Susumu Itoh;Masako Inamitsu et al.;Daisuke Noda et al.;Gudrun Valdimarsdottir et al.;Masako Inamitsu et al.;Daisuke Noda et al.;Gudrun Valdimarsdottir et al.;Daisuke Noda;Gudrun Valdimarsdottir;Masako Inamnitsu;Daisuke Noda et al.;Rita L.C.Carvalho et al.
• 通讯作者: Rita L.C.Carvalho et al.