CSF-1 RECEPTOR SIGNALLING AND G1 PROGRESSION

受体和细胞质酪氨酸激酶通过以下途径触发信号传导： 其他细胞关键调节因子的共同途径 增长 这些信号转换器共同控制着对 细胞外有丝分裂原，其驱动通过G1期的进展 细胞周期。 G1进展的关键限速调节剂 包括MYC、D型和E型G1细胞周期蛋白，以及它们的催化作用。 细胞周期蛋白依赖性激酶（CDK）伴侣。nih 3 t3成纤维细胞 表达突变的人集落刺激因子-1受体 [CSF-1 R（Y809 F）]在小鼠中表现出减弱的受体激酶活性， 对CSF-1的反应，并且当用 生长因子 这些CSF-1刺激的细胞保持活力， 经历各种立即早期反应基因的诱导，例如 作为FOS和Jun家族成员，但他们没有表现出MYC， 细胞周期蛋白D或E诱导，并保持在早期G1期阻滞。 救援的受体缺陷已确定共同的信号 传感器，包括MYC本身，ETS因子和D型 细胞周期蛋白，作为S 阶段进入。 我们将采用公正的方法来确定 信号通路的重要组成部分， CSF-1诱导MYC和细胞周期蛋白D功能的促有丝分裂信号。 表达CSF-1 R [Y809 F]的细胞将被逆转录病毒感染 编码哺乳动物cDNA文库，以及那些指定 能够有条件地拯救响应CSF的促有丝分裂性的蛋白质- 1将被识别。 将研究选定的基因的能力， 诱导MYC表达或绕过其功能。 许多积极 G1期进展调节因子（包括CSF-1 R、MYC和细胞周期蛋白 D1）突变时可作为协同致癌基因发挥作用， 组成性过表达，而其相反的负 调节剂起肿瘤抑制剂的作用。 因此，我们预计 新发现的促有丝分裂信号的转换器 当基因改变时， 或不恰当的表达。 新型效应物的鉴定 分子应该能够定义调控网络， G1阶段后期的事件，包括承诺进入S阶段。

Receptor and cytoplasmic tyrosine kinases trigger signaling through common pathways in which lie other critical regulators of cell growth. Together, these signal transducers govern the response to extracellular mitogens which drive progression through the G1 phase of the cell cycle. Critical rate limiting regulators of G1 progression include MYC, the D-and E-type G1 cyclins, and their catalytic cyclin-dependent kinase (CDK) partners. NIH3T3 fibroblasts expressing a mutant human colony-stimulating factor-1 receptor [CSF-1R (Y809F)] exhibit attenuated receptor kinase activity in response to CSF-1 and fail to proliferate when stimulated with the growth factor. These CSF-1 stimulated cells remain viable and undergo induction of various immediate early response genes, such as FOS and Jun family members, but they do not manifest MYC, cyclin D or E induction, and they remain arrested in early G1 phase. Rescue of the receptor defect has identified common signal transducers, including MYC itself, ETS factors, and the D-type cyclins, that act as essential downstream components required for S phase entry. We will utilize an unbiased approach to identify essential components of signaling pathways that functionally connect CSF-1 induced mitogenic signals to MYC and cyclin D function. Cells expressing CSF-1R[Y809F] will be infected with retroviruses encoding mammalian cDNA libraries, and those cDNAs that specify proteins able to conditionally rescue mitogenicity in response to CSF- 1 will be identified. Selected genes will be studied for their ability to induce MYC expression or to bypass its functions. Many positive regulators of G1 progression (including CSF-1R, MYC, and cyclin D1) can function as collaborating oncogenes when mutated or constitutively overexpressed, whereas their opposing negative regulators function as tumor suppressors. We therefore anticipate that newly identified transducers of mitogenic signals identified here will similarly be implicated in oncogenesis when genetically altered or inappropriately expressed. The identification of novel effector molecules should enable definition of regulatory networks that govern events late in G1 phase, including the commitment to enter S phase.