CONTROL OF STEM CELL PROLIFERATION BY CELL CYCLE INHIBITORS

有丝分裂细胞周期的进展是由被称为细胞周期蛋白依赖性蛋白激酶(CDKs)的蛋白激酶的酶活性驱动的。在静止的细胞中，这些激酶的活性通常由另一种蛋白质家族--环状激酶抑制物--来控制，该家族结合并使CDK失活。这个项目将重点放在一种循环激酶抑制剂p27kip1上，我们之前已经证明了它可以限制造血细胞的增殖。拟议的实验将确定我们的p27基因敲除小鼠中p27的丢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p27是否正常地调节干细胞的增殖，以响应可溶性生长因子或细胞外基质蛋白-纤维连接蛋白。我们还将研究p27在控制干细胞增殖中与其他细胞周期抑制蛋白协同作用的可能性。

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.