Cellular Functions of HCF

描述（由申请人提供）：本项目的总体目标是 了解HCF蛋白在细胞分裂和增殖中的功能。的 该家族的创始成员是人类单纯疱疹病毒（HSV）宿主 细胞因子HCF-1。HCF（也称为Cl，VCAF和CFF）是一种丰富的 在动物中高度保守的染色质相关蛋白。它是一个大型 经历涉及蛋白质水解的不寻常成熟过程的蛋白质， 结果：N-和C-末端HCF-1 N和HCF-1c多肽保持稳定 互相关联。Dunn HSV感染时，HCF-1起着重要作用， 在HSV立即-早期（IE基因通过 其与HSV反式激活因子VP 16的关联。在未感染的细胞中，HCF-1 在细胞分裂和增殖中起着关键作用， 染色质。HCF- 1不直接与DNA结合，而是与DNA结合。 与染色质通过一个定义的蛋白质-蛋白质相互作用模块， 结构域，也用于通过其相互作用将HCF-1拴系到HSV基因组 VP 16 HCF-1和相关的人类蛋白HCF-2共享一个保守的 秀丽隐杆线虫（Caelophabditis elegans）中的同源物，称为秀丽隐杆线虫C.秀丽隐杆线虫HCF（CeHCF）。损失 哺乳动物细胞系中HCF- 1功能和蠕虫中CeHCF功能的差异导致 胞质分裂和有丝分裂组蛋白磷酸化缺陷 提示Aurora B激酶-蛋白磷酸酶1（PP 1）被破坏 通路至少一些由HCF-1功能丧失引起的缺陷可以是 pRb肿瘤抑制因子的失活克服，这表明， HCF-1的作用是直接或间接地抑制pRb功能。因此，在本发明中， HCF-1似乎是细胞增殖的关键调节因子。本课题 将继续使用创新和互补的基因，分子和细胞 生物学和生物化学的方法来剖析的结构和功能， HCF蛋白在细胞分裂和增殖中起关键作用。我们 具体的目的是（i）研究HCF-1在胰岛细胞中的作用， 增殖和分化;（ii）识别和表征 哺乳动物细胞中HCF功能的效应物;并阐明 秀丽隐杆线虫中的HCF蛋白功能。

DESCRIPTION (provided by applicant): The overall goal of this project is to understand the function of HCF proteins in cell division and proliferatior. The founding member of this family is the human herpes simplex virus (HSV) host cell factor HCF-1. HCF(also known as Cl, VCAF, and CFF) is an abundant chromatin-associated protein that is highly conserved i animals. It is a large protein that undergoes an unusual maturation process involving proteolysis that results i N- and C-terminal HCF-1N and HCF-1c polypeptides that remain stably associated with one another. Dunn HSV infection, HCF-1 plays an important regulatory role in the transcription of HSV immediate-early (IE genes through its association with the HSV transactivator VP16. In uninfected cells, HCF-1 plays a critica role in cell division and proliferation through its association with chromatin. HCF- 1 does not association directly with DNA but associates with chromatin through a defined protein-protein interaction module, Keich domain, also used to tether HCF-1 to the HSV genome through its interaction with VP 16. HCF-1 and related human protein HCF-2 share a single conserved homolog in the worm Caenorhabditis elegans, called C. elegans HCF (CeHCF). Loss of HCF- 1 function in a mammalian cell line and CeHCF function in worm leads to similar defects in cytokinesis and mitotic histone phosphorylation - defects that suggest disruption o the Aurora B kinase-Protein Phosphatase 1 (PP1) pathway. At least some of the defects caused by loss o HCF-1 function can be overcome by inactivation of the pRb tumor suppressor, suggesting that a natural role o HCF-1 is to suppress pRb function, either directly or indirectly. Thus, HCF-1 appears to be a key regulator o cell proliferation. In this project, we will continue to use innovative and complementary genetic, molecula and cell biological, and biochemical approaches to dissect the structure and function of HCF proteins in thei critical roles in cell division and proliferation. Our specific aims are (i) to study the roles of HCF-1 i mammalian-cell proliferation and differentiation; (ii) to identify and characterize the effectors of HCFfunction in mammalian cells; and to elucidate the roles of HCF-protein function in Caenorhabditis elegans.