The Role of Ring domain AP-1 Coactivator (RACO)-1 in Lung cancer

肺癌是人类最常见的癌症之一。在20-30%的非小细胞肺癌中发现了K-RAS癌基因的激活突变。最近，在肺的细支气管肺泡管连接处发现了一群被称为细支气管肺泡干细胞的干细胞。有研究认为这些干细胞是K-RAS肺腺癌的前驱细胞。MAP激酶通路已被证明在控制这一细胞群体的动态平衡方面起着重要作用。AP-1转录因子被认为是致癌RAS信号的重要介导者，但致癌RAS与c-Jun/AP-1之间的分子联系尚不清楚。宿主实验室最近发现了一个以前未鉴定的蛋白质，命名为环域AP-1共激活因子(RACO)-1，它在Ras-Raf-MEK-ERK MAP激酶通路和AP-1激活之间起着分子联系的作用。在这项提案中，我将研究RACO-1在肺干细胞动态平衡和K-RAS诱导的肺肿瘤中的作用。这个项目的目标是了解两个明确定义的癌基因之间合作的分子机制。RAS和c-Jun/AP-1在一种高度相关和流行的癌症的发生发展中的作用。

Lung cancer is one of the most prevalent human cancers. Activating mutations of the K-Ras oncogene are found in 20-30% of non-small-cell lung cancers. Recently, a population of stem cells referred to as bronchioalveolar stem cells, has been identified at the bronchioalveolar duct junctions of the lung. It has been proposed that these stem cells are the precursors of K-Ras lung adenocarcinomas. MAP kinase pathways have been shown to be important in controlling the homeostasis of this cell population. The AP-1 transcription factor is believed to be an important mediator of oncogenic Ras signalling, however the molecular connection between oncogenic Ras and c-Jun/AP-1 has been unclear. The host lab has recently identified a previously uncharacterized protein, named Ring domain AP-1 Coactivator (RACO)-1 which functions as a molecular link between Ras-Raf-MEK-ERK MAP kinase pathways and AP-1 activation. In this proposal, I will investigate the role of RACO-1 in lung stem cell homeostasis and in K-Ras-induced lung tumours. The goal of this project is to understand the molecular mechanisms of co-operation between two well-defined oncogenes. Ras and c-Jun/AP-1, in the development of a highly relevant and prevalent form of cancer.