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J. Biol. Chem., Vol. 282, Issue 8, 5790-5800, February 23, 2007

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Individual Overexpression of Five Subunits of Human Translation Initiation Factor eIF3 Promotes Malignant Transformation of Immortal Fibroblast Cells^*

Lili Zhang, Xiaoyu Pan, and John W. B. Hershey¹

From the Department of Biochemistry and Molecular Medicine, School of Medicine, and the Department of Molecular and Cell Biology, University of California, Davis, California 95616

Transcriptional and post-transcriptional regulatory mechanisms are commonly accepted paradigms of tumorigenesis. The view is emerging that deregulation of translation contributes importantly to cancer development, a role not generally appreciated before. Eukaryotic initiation factor eIF3 contains at least thirteen non-identical subunits, named from eIF3a to eIF3m, and plays an essential role in the rate-limiting initiation phase of translation. Increased mRNA and protein levels of the eIF3a, -3b, -3c, -3h, and -3i subunits have been detected in a wide variety of human tumors and are frequently identified as prognostic biomarkers for poor clinical outcome. However, it remains to be established whether up-regulation of eIF3 subunits is a consequence or a cause of the malignant phenotypes. Here we report that ectopic expression of eIF3a, -3b, -3c, -3h, or -3i in stably transfected NIH3T3 cells leads to a number of oncogenic properties: decreased doubling times, increased clonogenicity and viability, facilitated S-phase entry, attenuation of apoptosis, formation of transformed foci, and anchorage-independent growth. Only overexpression of the transforming subunits results in a stimulation of initiation and global protein synthesis rates and enhanced translation of poorly translated mRNAs that encode growth-regulating proteins, including cyclinD1, c-Myc, fibroblast growth factor-2, and ornithine decarboxylase, which may be responsible for oncogenic malignancy in the transformed cell lines. Based on these results, we hypothesize that eIF3 contributes to hyperactivation of the translation initiation machinery and thereby may play an important role in neoplasia. Cancer cells appear to require an aberrantly activated translational state to survive, suggesting that the initiation factors may be promising therapeutic targets for treating cancer.

Received for publication, June 30, 2006 , and in revised form, December 14, 2006.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S6.

¹ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Medicine, School of Medicine, University of California-Davis, One Shields Ave., Davis, CA 95616. Tel.: 530-752-3235; Fax: 530-752-3516; E-mail: jwhershey{at}ucdavis.edu.

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