Cross-talk regulatory proteins that function for potentiation of IGF signals in stage-and tissue-specific manners

串扰调节蛋白，以阶段和组织特异性方式增强 IGF 信号

• 批准号: 13460124
• 负责人: TAKAHASHI Shin-ichiro
• 金额: $ 9.79万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13460124/
• 关键词: insulin-like growth factor; tropic hormone; cAMP; signal cross-talk; intracellular signal; tyrosine phosphorylation; cell growth; kinase

The biological effects of IGFs in endocrine cells are often potentiated in the presence of tropic hormones. In previous studies, we showed that pretreatment of rat FRTL-5 thyroid cells with TSH or CAMP generating agents markedly potentiated DNA synthesis induced by IGF-I. Under these conditions, we found that CAMP stimulus activated PI 3-kinase by binding of tyrosine-phosphorylated p125, and this PI 3-kinase activation was indispensable for the potentiation of DNA synthesis induced by following IGF-I stimulus. In addition, our recent results suggested that PI 3-kinase activity in response to IGF-I was augmented by cAMP pretreatment though binding IRS-2 to IRS-associated proteins, leading to potentiation of IRS-2 tyrosine phosphorylation by IGF-I receptor and this augmented IGF-I-responsive PI 3-kinase activity was also essential for synergistic DNA synthesis induced by cAMP and IGF-I. cAMP pretreatment enhanced IGF-I-dependent increases in G1 Cyclins, Cyclin D1 and E, and decrease in o … More ne of CDK inhibitors, p27^<Kip1>, resulting in marked activation of G1 Cyclins-associated CDK followed by Rb phosphorylation. Further analysis demonstrated that cAMP pretreatment enhanced IGF-I-dependent increases in G1 Cyclins mRNA levels and the formation of Cyclin D1 mRNA-polysome.complex. cAMP-dependent enhancement of decrease in p27^<Kip1> induced by IGF-I was mainly caused by a synergistic degradation of p27^<Kip1> through the ubiquitin-proteasome pathway. Our results using a PI 3-kinase inhibitor showed that IGF-I-dependent PI 3-kinase activation was required for synergistic changes in G1 Cyclins mRNA levels, and p27^<Kip1> degradation. In contrast, cAMP-dependent P13-kinase activation may play an important role for an increase in Cyclin D1 translation. Taken together, the present study demonstrated that PI 3-kinase controlled by cAMP or IGF-I stimulus play different roles for synergistic changes in G1 Cyclins and p27^<Kip1> leading to cAMP-dependent potentiation of DNA synthesis induced by IGF-I. From this study, we propose that p125 and IRS-associated proteins play important roles in cross-talk between IGFs and tropic hormones in an endocrine system. Less

在促性腺激素的存在下，IGFS在内分泌细胞中的生物学效应经常被增强。在以前的研究中，我们发现用TSH或cAMP生成剂预处理大鼠FRTL-5甲状腺细胞可以显著增强IGF-I诱导的DNA合成。在此条件下，我们发现cAMP刺激通过与酪氨酸磷酸化的p125结合来激活PI3K，这种PI3K的激活对于随后的IGF-I刺激诱导的DNA合成的增强是不可或缺的。此外，我们最近的研究结果表明，cAMP通过将IRS-2与IRS相关蛋白结合，使IGF-I受体激活IRS-2酪氨酸磷酸化，从而增强IGF-I诱导的PI 3-K活性，这种增强的PI 3-K活性对cAMP和IGF-I诱导的DNA合成的协同作用也是必不可少的。CAMP预处理促进胰岛素样生长因子I依赖的G1期细胞周期蛋白、细胞周期蛋白D_1和细胞周期蛋白E的增加以及细胞周期蛋白O_…的减少更多的CDK抑制剂，p27^和lt；Kip1和gt；，导致G1周期蛋白相关的CDK显著激活，随后Rb磷酸化。进一步分析表明，cAMP预处理可增强IGF-I依赖的G1期细胞周期蛋白基因表达水平的升高，并促进细胞周期蛋白D1mRNA-多聚体复合体的形成。IGF-I诱导的p27^&lt；Kip1&gt；的cAMP依赖性增强主要是通过泛素-蛋白酶体途径使p27^&lt；Kip1和gt；协同降解所致。我们使用PI 3-激酶抑制剂的结果显示，依赖于IGF-I的PI-3-Kinase激活是G1期细胞周期蛋白mRNA水平协同变化和p27；相反，cAMP依赖的P13-激酶的激活可能在增加Cyclin D1的翻译中起着重要作用。综上所述，本研究证实了由cAMP或IGF-I刺激控制的PI3-K在G1期细胞周期蛋白和p27^-lt；Kip1&gt；的协同变化中发挥不同的作用，从而导致IGF-I诱导的cAMP依赖的DNA合成增强。通过这项研究，我们认为p125和IRS相关蛋白在IGFS和内分泌系统中的热带激素之间的串扰中起着重要的作用。较少

项目成果

高橋伸一郎 他: "甲状腺細胞の増殖とcAMP特異的ホスホジエステラーゼ"ホルモンと臨床. 50. 183-191 (2002)

Shinichiro Takahashi 等人：“甲状腺细胞增殖和 cAMP 特异性磷酸二酯酶”激素与临床科学 50. 183-191 (2002)。

Suzuki N. et al.: "Novel mechanisms of insulin resistance in chronically GH-treated 3T3-L1 adipocytes"GH IGF Res.. 12. 280 (2002)

Suzuki N. 等人：“长期 GH 处理的 3T3-L1 脂肪细胞中胰岛素抵抗的新机制”GH IGF Res.. 12. 280 (2002)

高橋伸一郎: "標的細胞近傍でのIGFBPsの生理機能、そしてIGFBPsとIGFBP-rPsのIGFを介さない新しい生理活性"PRISM. 4. 5-6 (2001)

Shinichiro Takahashi：“靶细胞附近 IGFBP 的生理功能以及 IGFBP 和 IGFBP-rP 不受 IGF 介导的新生理活性” PRISM 4. 5-6 (2001)。

高橋伸一郎: "インスリン様成長因子結合タンパク質の構造と機能"内分泌・糖尿病科. 15. 110-122 (2002)

高桥真一郎：“胰岛素样生长因子结合蛋白的结构和功能”内分泌和糖尿病系15。110-122（2002）。

高橋伸一郎: "インスリン様成長因子結合タンパク質の構造と機能"内分泌・糖尿病科. 15. 110-122 (2003)

高桥真一郎：“胰岛素样生长因子结合蛋白的结构和功能”内分泌和糖尿病系15。110-122（2003）。