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Molecular mechanism of cell cycle regulation in human T cells

人类T细胞细胞周期调控的分子机制

基本信息

批准号：
12670296
负责人：
NAKAMURA Masataka
金额：
$ 2.18万
依托单位：
Tokyo Medical and Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670296/
关键词：
T lymocytes Cell cycle IL-2 E2F CDK CDK inhibitor Rb リン酸化

项目摘要

Molecular mechanism of the cell cycle and cell growth has been studied mainly with fibroblastic cells. The mechanism is applicable to lymphocytes except for some points ; for example overexpression of a cell cycle transcription factor E2F1 induces cell cycle progression in rat fibroblasts but not in human T cells. We studied the molecular mechanism of IL-2-induced cell cycle progression in human T cells. IL-2 induced activation of E2F4, which was inactivated in resting phase by the fomation of complex with p130, a member of the Rb family. Once treated with IL-2, T cells reduced levels of cyclin-dependent kinase (CDKs), p19 and p27, and increased expression of genes for CDKs and D-type cyclins, resulting in induction of CDK activities. Activated CDKs phosphorylated the pRb family members, p130, p107 and pRb, which led release of active form of E2F4 from the complex with p130. Indeed, we observed, when T cells were stimulated with IL-2, a decrease in amount of the complex consisting of E2F4 and p130, which is thought to be a resting type complex, and an increase in amount of free E2F4 molecules, which showed the ablity to bind DNA elements. In addition, IL-2 brought transition of the E2F complex to S phase one containing E2F4, p130, p107, CDK2 and cyclin A. Collectively, IL-2 induces a chain reaction to activate E2F that leads cell cycle progression and cell growth by triggering activation of CDKs.

细胞周期和细胞生长的分子机制主要以成纤维细胞为研究对象。该机制适用于淋巴细胞，除了某些点;例如，细胞周期转录因子E2 F1的过表达诱导大鼠成纤维细胞的细胞周期进展，但不诱导人T细胞的细胞周期进展。我们研究了IL-2诱导人T细胞细胞周期进程的分子机制。IL-2诱导E2 F4活化，E2 F4在静息期通过与Rb家族成员p130形成复合物而失活。一旦用IL-2处理，T细胞降低细胞周期蛋白依赖性激酶（CDK）、p19和p27的水平，并增加CDK和D型细胞周期蛋白的基因表达，导致诱导CDK活性。活化的CDK使pRb家族成员p130、p107和pRb磷酸化，这导致活性形式的E2 F4从与p130的复合物中释放。事实上，我们观察到，当用IL-2刺激T细胞时，由E2 F4和p130组成的复合物的量减少，该复合物被认为是静息型复合物，而游离E2 F4分子的量增加，其显示出结合DNA元件的能力。另外，IL-2使E2 F复合物转变为含有E2 F4、p130、p107、CDK 2和cyclin A的S期1。总的来说，IL-2诱导链式反应以激活E2 F，E2 F通过触发CDK的激活而导致细胞周期进展和细胞生长。