| Co-Investigator(Kenkyū-buntansha) |
HAKUNO Fumihiko The University of Tokyo, Graduate School of Agriculture and life Sciences, Assistant, 大学院・農学生命科学研究科, 助手 (30282700)
KATAOKA Hiroshi The University of Tokyo, Graduate School of Frontier Sciences, Professor, 大学院・新領域創成科学研究科, 教授 (60202008)
NISHIHARA Masugi The university of Tokyo, Graduate School of Agriculture and Life Sciences, Professor, 大学院・農学生命科学研究科, 教授 (90145673)
FURUKUBO-TOKUNAGA Katsuo (徳永 克男) University of Tsukuba, Institute of Biological Sciences, Associate Professor, 生物科学系, 助教授 (00272154)
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| Research Abstract |
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
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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
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