Role of p170 in lung tumorigenesis

描述(由申请人提供)：基因表达可以在转录和翻译水平上进行调节。大多数翻译调控发生在翻译启动的层面上。与转录因子不同，真核细胞翻译起始因子(EIF)在控制细胞生长方面的作用尚未得到很好的认识。最近的研究表明，elF4E、eIF2和eIF3的P48亚基可能参与了细胞生长控制和肿瘤的发生。最近，人们发现eIF3可能的亚单位P170在人类肺癌、乳腺癌、宫颈癌和食道癌中表达上调。我们观察到P170可能是核糖核苷酸还原酶M2表达的重要调节因子。因此，eIF3 P170可能是控制细胞生长调节蛋白表达的重要调节因子，从而调控细胞生长。该项目的长期目标是确定eIF3P170在细胞生长控制中的作用及其与人类癌症的关系。需要检验的假设是，P170是调节特定细胞生长控制蛋白合成的主要参与者。为此，我们计划在资助期内完成以下具体目标：(1)确定pl70的过度表达是否导致肿瘤发生；(2)确定p170是否通过控制DNA合成酶(如核糖核苷酸还原酶M2)的合成来调节细胞生长；以及(3)研究eIF3 p170的表达调控。一种假定的管家蛋白P170在肿瘤发生中的作用以前没有被提出，因此这项研究是新的。从本研究中获得的信息和探针将有助于我们理解翻译调控细胞生长的分子机制。这项工作肯定会加深我们对蛋白质合成中翻译起始的作用机制的理解。

DESCRIPTION (provided by applicant): Gene expression can be regulated at both the transcriptional and translational level. Most of the translational regulation occurs at the level of translation initiation. Unlike transcription factors, eukaryotic translation Initiation Factors (eIF) have not been well recognized for their role in controlling cell growth. Recent studies suggest that elF4E, eIF2, and the p48 subunit of eIF3 may be involved in cell-growth control and oncogenesis. More recently, the expression of the putative subunit p170 of eIF3 was found to be up regulated in human lung, breast, cervical, and esophageal cancers. We have observed that p170 may be an important regulator for the expression of ribonucleotide reductase M2. Thus, eIF3 p170 may be an important regulator for controlling the expression of cell growth regulatory proteins and, thus, cell growth. The long-term goal of this project is to establish the role of eIF3 p170 in cell growth control and its relationship to human cancer. The hypothesis to be tested is that p170 is a major player in regulating the synthesis of specific cell growth control proteins. To this end, we plan to accomplish the following specific aims within the funding period: (1) to determine whether over-expression of pl70 causes tumorigenesis; (2) to determine whether p 170 regulates cell growth by controlling the synthesis of DNA synthesis enzymes such as ribonucleotide reductase M2; and (3) to study the regulation of eIF3 p170 expression. The role of a putative housekeeping protein, p170, in tumorigenesis has not been suggested previously and thus this study is novel. The information and probes obtained from this study will help us understand the molecular mechanism of translational control of cell growth. This work will certainly add to our understanding of the functional mechanism of translation initiation of protein synthesis.