Interaction of TCL1 with a novel exoribonuclease

描述(由申请者提供)：项目摘要：本建议书描述了一项为期3年的计划，旨在培养候选人成为肿瘤生物学领域的独立研究员。除了在匹兹堡大学完成分子生物学博士学位外，这位候选人还完成了为期一年的肝脏和胃肠病理学住院医师培训，并在加州大学洛杉矶分校从事肝脏和胃肠病理学近三年的实践。在此期间，他在Michael Teitell博士的实验室从事博士后基础研究，研究癌基因TCL1的调节及其在癌症发生中的作用。这一拟议的计划将允许候选人开发一项超出TCL1范围的独立研究计划。这项研究将集中在一种新发现的线粒体外切核酸酶PNPase在TCL1介导的恶性转化中所起的作用。泰特尔实验室最近的工作帮助表征了一种新的TCL1转基因小鼠模型，该模型可以从生发中心B细胞发展成不同类型的成熟B细胞恶性肿瘤。这个模型显示了一个重要的增殖和细胞生存蛋白激酶AKT的激活增加，突出了TCL1介导的肿瘤形成的一个潜在机制。最近，候选人发现了第三种蛋白质，称为多核苷酸磷酸化酶(PNPase)，它直接与TCL1结合。拟进行的实验将包括确定PNPase在TCL1/AKT介导的转化信号通路中所起的作用，以及确定PNPase本身与TCL1相关的独特生物学。这将为候选人作为研究人员提供坚实的、独立的工作基础。其具体目的包括：1)确定PNPase在TCL1/AKT复合体形成和AKT激活中的作用；2)确定TCL1/PNPase复合体的形成作用；3)确定TCL1/PNPase在基因调控中的作用。相关性：癌症的发展方式之一是通过细胞内通讯系统组件的水平和活动的变化来决定它是生长、停止生长还是死亡。这项研究将有助于理解这些细胞成分之一TCL1在与新发现的信号成分PNPase相互作用时发出细胞癌变信号的机制。

DESCRIPTION (provided by applicant): Project summary: This proposal describes a 3 year program for the development of the candidate as an independent investigator in Tumor Biology. In addition to completing a Ph.D. in Molecular Biology at the University of Pittsburgh, the candidate has completed residency training in Anatomic Pathology, a year-long fellowship in Liver and Gastrointestinal Pathology, and has practiced Liver and Gastrointestinal Pathology for almost three years at the University of California at Los Angeles. During this time he has engaged in postdoctoral basic research in the laboratory of Dr. Michael Teitell studying the regulation of the oncogene TCL1 and its role in carcinogenesis. This proposed program will allow the candidate to develop an independent research program beyond the scope of TCL1. The research will focus on the role that a newly identified mitochondrial exoribonuclease, PNPase, plays in TCL1-mediated malignant transformation. Recent work in the Teitell lab helped characterize a new TCL1 transgenic mouse model that develops distinct types of mature B-cell malignancies from germinal center B-cells. This model shows an increased activation of an essential proliferation and cell survival protein kinase, AKT, highlighting a potential mechanism in TCL1-mediated tumor formation. More recently, the candidate identified a third protein, termed polynucleotide phosphorylase (PNPase), that directly binds TCL1. The proposed experiments will involve determination of the role PNPase plays in the signaling pathway of TCL1/AKT mediated transformation as well as defining the unique biology of PNPase itself as it related to TCL1. This will provide a firm, separate foundation of work for the candidate to function as an researcher. The specific aims include: 1) Determining the role of PNPase in TCL1/AKT complex formation and AKT activation; 2) Determining the effects of TCL1/PNPase complex formation; and 3) Determining the effect of TCL1/PNPase on gene regulation. Relevance: One of the ways that cancer develops is through changes in levels and activity of the components of the communication system within a cell that determines whether it grows, stops growing, or dies. This study will allow for understanding the mechanism by which one of these cell components, TCL1, signals a cell to become cancerous in its interaction with a newly identified signaling component PNPase.