Cytokine Signaling

说明(申请人提供)：I型干扰素(IFN)是抵御病毒感染的第一道防线，在调节细胞增殖方面发挥重要作用。这两种作用都需要激活Jak-STAT通路，然而，IFN激活了其他也参与其抗病毒和抗增殖功能的通路。I型干扰素抑制肿瘤细胞生长的机制尚不完全清楚。此外，根据环境的不同，干扰素可以具有细胞抑制作用，诱导细胞凋亡，也可以完全抵抗细胞。为了发现可能干预I型IFN生物学效应的新蛋白，我们进行了以干扰素-R链为诱饵的双杂交筛选。我们已经克隆了一个名为Bara的基因。BARA与I型干扰素受体的β链相互作用。在线虫中，BarA的同源物是Cyclin D-CDK4-视网膜母细胞瘤(Rb)途径(称为途径B)的一部分，该途径与另一条冗余途径(称为途径A)一起负向调节细胞周期进展和外阴发育。本项目将重点研究BARA在I型干扰素抑制细胞生长中的作用。 在特定目的1中，我们将确定BarA在干扰素诱导的生长抑制、细胞凋亡和细胞衰老中的作用。 在特定的目标2中，我们将检验这样的假设，即干扰素系统是哺乳动物中相当于线虫中负向调节EGF-Ras-MAPK途径的途径(途径B)。 在特定的目标3中，我们将确定BarA基因纯合缺失的小鼠是否有干扰素系统的变化。我们预计，这项提议将实现的目标将有助于理解I型IFN的增长调控效应。

DESCRIPTION (provided by applicant): Type I Interferons (IFNs) are the first line of defense against viral infections and play an important role in the regulation of cell proliferation. Both effects require the activation of the Jak-STAT pathway however, IFNs activate other pathways that also intervene in its antiviral and antiproliferative functions. The mechanism of the growth inhibitory action of type I IFNs is not completely clear. Moreover, depending on the context, IFNs can have either a cytostatic effect, induce apoptosis, or cells can be completely resistant. In order to discover new proteins that may intervene in the biological effects of type I IFNs, we performed a two-hybrid screening using the IFN-R chains as bait. We have cloned a gene termed BARA. BARA interacts with the betaL chain of the type I interferon receptor. The homolog of BARA in C. elegans is part of the Cyclin D-CDK4-retinoblastoma (RB) pathway (termed pathway B), which in conjunction with another redundant pathway (termed pathway A) negatively regulate cell cycle progression and vulval development. This project will focus on the role of BARA on the cell growth inhibitory effects of type I IFNs. In Specific Aim 1 we will determine the role of BARA in IFN-induced growth inhibitory effect, apoptosis and cell senescence. In Specific Aim 2 we will test the hypothesis that the IFN system is the mammalian equivalent to a pathway (pathways B) that in C. elegans negatively regulates EGF-RAS-MAPK pathway. In Specific Aims 3 we will determine if mice with a homozygous deletion of the BARA gene have alterations of the IFN system. We expect that the goals to be achieved with this proposal will shed light on the understanding of the growth regulatory effects of type I IFNs.