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

内分泌细胞中IGFs的生物学效应通常在促激素存在下增强。在以前的研究中，我们发现用TSH或CAMP产生剂预处理大鼠FRTL-5甲状腺细胞显著增强IGF-I诱导的DNA合成。在这些条件下，我们发现cAMP刺激通过酪氨酸磷酸化的p125结合激活PI 3-激酶，并且这种PI 3-激酶激活对于随后的IGF-I刺激诱导的DNA合成增强是必不可少的。此外，我们最近的研究结果表明，cAMP预处理可通过IRS-2与IRS-相关蛋白的结合增强IGF-I对IRS-2酪氨酸磷酸化的作用，从而增强IGF-I对PI-3-激酶活性的应答，这种增强的IGF-I应答性PI-3-激酶活性对cAMP和IGF-I诱导的协同DNA合成也是必需的。cAMP预处理增强了IGF-I依赖的G1期细胞周期蛋白，细胞周期蛋白D1和E的增加，以及细胞周期蛋白D1和E的减少。 关于我们 一种CDK抑制剂，p27 β<Kip1>，导致G1期细胞周期蛋白相关的CDK显著活化，随后Rb磷酸化。进一步的分析表明，cAMP预处理增强IGF-I依赖性增加G1细胞周期蛋白mRNA水平和细胞周期蛋白D1 mRNA-多聚体的形成。cAMP依赖性增强IGF-I诱导的p27 α的降低<Kip1>主要是<Kip1>通过泛素-蛋白酶体途径协同降解p27 α引起的。我们使用PI 3-激酶抑制剂的结果表明，IGF-I依赖的PI 3-激酶激活是G1细胞周期蛋白mRNA水平和p27 β降解的协同变化所必需<Kip1>的。相反，cAMP依赖性P13激酶激活可能在细胞周期蛋白D1翻译增加中发挥重要作用。综上所述，本研究表明，由cAMP或IGF-1刺激控制的PI 3-激酶在G1 Cyclins和p27 β的协同变化中发挥不同的作用，<Kip1>导致cAMP依赖性IGF-1诱导的DNA合成增强。从这项研究中，我们提出，p125和IRS相关蛋白发挥重要作用，在胰岛素样生长因子和热带激素的内分泌系统之间的串扰。少

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