CONTROL OF STEM CELL PROLIFERATION BY CELL CYCLE INHIBITORS

通过有丝分裂细胞周期的进展是由称为细胞周期蛋白依赖性激酶（CDK）的蛋白激酶的酶活性驱动的。这些激酶的活性通常在静止细胞中由另一个蛋白质家族，即结合和抑制CDK的环激酶抑制剂来控制。这个项目将集中在一个循环激酶抑制剂，p27kip1，我们以前显示的行为，以限制造血细胞的增殖。拟议的实验将确定在我们的p27基因敲除小鼠中，p27的缺失是否会导致造血干细胞的异常细胞增殖。我们将使用体外和体内的方法来确定是否p27正常调节干细胞增殖的可溶性生长因子或细胞外基质蛋白，纤连蛋白。还将研究p27与其他细胞周期抑制蛋白在控制干细胞增殖中的合作潜力。

Progression through the mitotic cell cycle is driven by the enzymatic activity of protein kinases known as the cyclin dependent kinases (CDKs). The activity of these kinases is normally kept in check in quiescent cells by another family of proteins, the cyclic kinase inhibitors, which bind and inactivate CDKs. This project will focus on a cyclic kinase inhibitor, p27kip1, which we have previous shown acts to limit proliferation in hematopoietic cells. The proposed experiments will determine whether loss of p27, in our p27 knockout mice, will lead to abnormal cell proliferation in hematopoietic stem cells. We will use both in vitro and in vivo methods to determine whether p27 normally regulates the proliferation of stem cells in response to soluble growth factors or the extracellular matrix protein, fibronectin. The potential for p27 to cooperate with other cell cycle inhibitory proteins in the control of stem cell proliferation will also be investigated.