Molecular mechanism of cell cycle regulation in human T cells

细胞周期和细胞生长的分子机制主要是用成纤维细胞来研究的。这种机制适用于淋巴细胞，除了某些点；例如，细胞周期转录因子E2F1的过表达可以诱导大鼠成纤维细胞的细胞周期进程，而不是人类T细胞的细胞周期进程。我们研究了IL-2诱导人T细胞周期进程的分子机制。IL-2诱导E2F4激活，静止期E2F4通过与Rb家族成员p130形成复合体而失活。经IL-2处理后，T细胞的细胞周期蛋白依赖性激酶(CDKs)、p19和p27水平降低，CDKs和D型细胞周期蛋白基因表达增加，从而诱导CDK活性。活化的CDK使pRb家族成员p130、p107和pRb磷酸化，导致活性形式的E2F4从与p130的复合体中释放出来。事实上，我们观察到，当T细胞被IL-2刺激时，由E2F4和p130组成的复合体的数量减少，这被认为是休止型复合体，而自由的E2F4分子的数量增加，表明有能力结合DNA元件。此外，IL-2还导致E2F复合体向S一期过渡，其中包括E2F4、p130、p107、CDK2和细胞周期蛋白A。IL-2通过激活CDKs，共同诱导连锁反应激活E2F，从而导致细胞周期进展和细胞生长。

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.