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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA094961-05
Application #
7252080
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Spalholz, Barbara A
Project Start
2003-09-30
Project End
2009-06-30
Budget Start
2007-07-01
Budget End
2009-06-30
Support Year
5
Fiscal Year
2007
Total Cost
$285,759
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Pharmacology
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Qi, J; Dong, Z; Liu, J et al. (2014) EIF3i promotes colon oncogenesis by regulating COX-2 protein synthesis and ?-catenin activation. Oncogene 33:4156-63
Dong, Zizheng; Qi, Jing; Peng, Hui et al. (2013) Spectrin domain of eukaryotic initiation factor 3a is the docking site for formation of the a:b:i:g subcomplex. J Biol Chem 288:27951-9
Yin, Ji-Ye; Dong, Zi-Zheng; Liu, Ran-Yi et al. (2013) Translational regulation of RPA2 via internal ribosomal entry site and by eIF3a. Carcinogenesis 34:1224-31
Liu, Ran-Yi; Dong, Zizheng; Liu, Jianguo et al. (2013) Overexpression of asparagine synthetase and matrix metalloproteinase 19 confers cisplatin sensitivity in nasopharyngeal carcinoma cells. Mol Cancer Ther 12:2157-66
Liu, R-Y; Dong, Z; Liu, J et al. (2011) Role of eIF3a in regulating cisplatin sensitivity and in translational control of nucleotide excision repair of nasopharyngeal carcinoma. Oncogene 30:4814-23
Yin, Ji-Ye; Dong, Zizheng; Liu, Zhao-Qian et al. (2011) Translational control gone awry: a new mechanism of tumorigenesis and novel targets of cancer treatments. Biosci Rep 31:1-15
Neher, Tracy M; Shuck, Sarah C; Liu, Jing-Yuan et al. (2010) Identification of novel small molecule inhibitors of the XPA protein using in silico based screening. ACS Chem Biol 5:953-65
Dong, Zizheng; Liu, Zhaoqian; Cui, Ping et al. (2009) Role of eIF3a in regulating cell cycle progression. Exp Cell Res 315:1889-94
Liu, Hailan; Liu, Yang; Zhang, Jian-Ting (2008) A new mechanism of drug resistance in breast cancer cells: fatty acid synthase overexpression-mediated palmitate overproduction. Mol Cancer Ther 7:263-70
Zhang, Jian-Ting; Liu, Yang (2007) Use of comparative proteomics to identify potential resistance mechanisms in cancer treatment. Cancer Treat Rev 33:741-56

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