Interaction of TCL1 with a novel exoribonuclease

描述（由申请人提供）：项目摘要：本提案描述了一个为期3年的计划，用于培养候选人作为肿瘤生物学的独立研究者。除了完成博士学位外，在匹兹堡大学的分子生物学专业，候选人已经完成了解剖病理学的住院医师培训，为期一年的肝脏和胃肠道病理学奖学金，并在洛杉矶的加州大学从事肝脏和胃肠道病理学近三年。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TCL 1的调控及其在致癌作用中的作用。这个拟议的计划将允许候选人开发一个独立的研究计划超出了TCL 1的范围。这项研究将集中在一个新发现的线粒体核糖核酸外切酶，PND 3，在TCL 1介导的恶性转化中发挥的作用。Teitell实验室最近的工作有助于表征一种新的TCL 1转基因小鼠模型，该模型从生发中心B细胞中产生不同类型的成熟B细胞恶性肿瘤。该模型显示了一种重要的增殖和细胞存活蛋白激酶AKT的激活增加，突出了TCL 1介导的肿瘤形成的潜在机制。最近，候选人确定了第三种蛋白质，称为多核苷酸磷酸化酶（PNIPs），直接结合TCL 1。所提出的实验将涉及确定PND 3在TCL 1/AKT介导的转化的信号传导途径中所起的作用，以及定义PND 3本身与TCL 1相关的独特生物学。这将为候选人提供一个坚实的，独立的工作基础，作为一名研究人员。具体目标包括：1）确定PND 3在TCL 1/AKT复合物形成和AKT活化中的作用; 2）确定TCL 1/PND 3复合物形成的作用;和3）确定TCL 1/PND 3对基因调控的作用。相关性：癌症发展的方式之一是通过细胞内通信系统成分的水平和活动的变化来决定它是否生长，停止生长或死亡。这项研究将允许了解这些细胞成分之一，TCL 1，信号细胞在其与新鉴定的信号成分PND 3的相互作用中癌变的机制。

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.