Distinct modes of activation of phosphatidylinositol 3-kinase in response to cyclic adenosine 3', 5'-monophosphate or insulin-like growth factor I play different roles in regulation of cyclin D1 and p27Kip1 in FRTL-5 cells.
Distinct modes of activation of phosphatidylinositol 3-kinase in response to cyclic adenosine 3', 5'-monophosphate or insulin-like growth factor I play different roles in regulation of cyclin D1 and p27Kip1 in FRTL-5 cells.
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磷脂酰肌醇 3-激酶响应环腺苷 3, 5-单磷酸或胰岛素样生长因子 I 的不同激活模式在 FRTL-5 细胞中细胞周期蛋白 D1 和 p27Kip1 的调节中发挥不同的作用。
作者：
T. Fukushima;T. Nedachi;Hidenori Akizawa;M. Akahori;F. Hakuno;Shin
IGFS在各种细胞中的生物活性通常在其他激素存在的情况下得到增强。在以前的研究中，我们发现用TSH或其他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，我们发现磷脂酰肌醇(PI)3-激酶在cAMP或IGF刺激下都被激活，并且这两种激活方式对于DNA合成的增强是不可或缺的。本研究旨在阐明cAMP和/或IGF-I刺激对G1期细胞周期蛋白依赖性激酶(CDK)抑制系统的调节作用，以及cAMP和IGF-I刺激激活PI-3-K在该系统中的作用。我们发现，cAMP预处理增强了细胞周期蛋白D1中IGF-I依赖性的增加，这是由于其协同作用增加了mRNA的表达和提高了翻译效率。此外，cAMP预处理增强了IGF-I诱导的CDK抑制物p27(Kip1)的蛋白降解。这些变化很好地解释了Cyclin E的增加，导致了G1 CDKs的显著激活，随后是视网膜母细胞瘤蛋白的磷酸化。我们使用PI3K抑制剂的结果表明，依赖cAMP的PI3K激活在细胞周期蛋白D1翻译的增加中起着重要作用。相反，细胞周期蛋白D1mRNA水平的升高和p27(Kip1)的降解需要依赖于IGF-I的PI3K的激活。综上所述，本研究阐明了cAMP和IGF-I作为多个分子事件的中介体在差异激活PI3-激酶中的作用。这些事件在细胞周期蛋白D1和p27(Kip1)的调控中汇聚，导致依赖cAMP的IGF-I依赖的CDK激活和DNA合成的增强。
Bioactivities of IGFs in various cells are often potentiated in the presence of other hormones. In previous studies we showed that pretreatment of rat FRTL-5 thyroid cells with TSH or other cAMP-generating agents markedly potentiated DNA synthesis induced by IGF-I. Under these conditions we found that phosphatidylinositol (PI) 3-kinase was activated in response to either cAMP or IGF stimulus, and both activation modes were indispensable for the potentiation of DNA synthesis. The present studies were undertaken to elucidate how cAMP and/or IGF-I stimulus regulated the G1 cyclin-cyclin dependent kinase (CDK)-inhibitor system, and to determine the roles of PI 3-kinase activation by cAMP or IGF-I stimulus in this system. We found that cAMP pretreatment enhanced IGF-I-dependent increases in cyclin D1, due to synergistic increases in mRNA and elevation of translation rates. Furthermore, cAMP pretreatment enhanced IGF-I-induced protein degradation of the CDK inhibitor, p27(Kip1). These changes well explained an increase in cyclin E, leading to marked activation of G1 CDKs, followed by retinoblastoma protein phosphorylation. Our results using a PI 3-kinase inhibitor showed that cAMP-dependent PI 3-kinase activation plays an important role in the increase in cyclin D1 translation. In contrast, IGF-I-dependent PI 3-kinase activation was required for the increase in cyclin D1 mRNA levels and degradation of p27(Kip1). Together, the present study elucidates the role of cAMP and IGF-I in differentially activating PI 3-kinase as a mediator of multiple molecular events. These events converge in the regulation of cyclin D1 and p27(Kip1), leading to cAMP-dependent potentiation of IGF-I-dependent CDK activation and DNA synthesis.
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影响因子：
10.5
作者：
Montagnoli, A;Fiore, F;Pagano, M
通讯作者：
Pagano, M
影响因子：
20.3
作者：
John I. Jones;D. Clemmons
通讯作者：
John I. Jones;D. Clemmons
影响因子：
3.7
作者：
Bonassar, LJ;Trippel, SB
通讯作者：
Trippel, SB
环腺苷 3,5-单磷酸对 p70 核糖体 S6 激酶的不同影响。
DOI：
10.1210/endo.139.4.5880
发表时间：
1998
期刊：
Endocrinology.
影响因子：
--
作者：
Cass,LA;Meinkoth,JL
通讯作者：
Meinkoth,JL
影响因子：
10.5
作者：
Diehl, JA;Cheng, MG;Sherr, CJ
通讯作者：
Sherr, CJ