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J. Biol. Chem., Vol. 283, Issue 35, 24047-24060, August 29, 2008

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An Oncogenic Role for the Phosphorylated h-Subunit of Human Translation Initiation Factor eIF3^*

Lili Zhang¹, Zeljka Smit-McBride, Xiaoyu Pan^¶, Jeanette Rheinhardt^||2, and John W. B. Hershey³

From the Department of Biochemistry and Molecular Medicine, Department of Ophthalmology and Vision Science, ^¶Department of Molecular and Cell Biology, and ^||Department of Pathology, School of Medicine, University of California, Davis, California 95616

Dysregulation of protein synthesis has been implicated in oncogenesis through a mechanism whereby "weak" mRNAs encoding proteins involved in cell proliferation are strongly translated when the protein synthesis apparatus is activated. Previous work has determined that many cancer cells contain high levels of eIF3h, a protein subunit of translation initiation factor eIF3, and overexpression of eIF3h malignantly transforms immortal NIH-3T3 cells. This is a general feature of eIF3h, as high levels also affect translation, proliferation, and a number of malignant phenotypes of CHO-K1 and HeLa cells and, most significantly, of a primary prostate cell line. Furthermore, overexpressed eIF3h inhibits Myc-dependent induction of apoptosis of primary prostate cells. eIF3h appears to function through translation, as the initial appearance of overexpressed eIF3h in rapidly induced NIH-3T3 cells correlates tightly with the stimulation of protein synthesis and the generation of malignant phenotypes. This oncogenic potential of eIF3h is enhanced by phosphorylation at Ser¹⁸³. Finally, reduction of eIF3h levels in breast and prostate cancer cell lines by short interfering RNA methods reduces their rates of proliferation and anchorage-independent growth in soft agar. The results provide compelling evidence that high eIF3h levels directly stimulate protein synthesis, resulting in the establishment and maintenance of the malignant state in cells.

Received for publication, February 5, 2008 , and in revised form, June 9, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants GM22135 and GM07373 (to J. W. B. H.). This work was also supported by American Cancer Society Grant IRG 95-125-04 from the Institutional Research Grant Program (to Z. S. M.) and by the Dean, University of California Davis School of Medicine. 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-S4 and additional references.

¹ Present address: Dept. of Obstetrics and Gynecology, University of California, San Francisco, CA 94143.

² Present address: Novartis Institute for Biomedical Science, Inc., 250 Massachusetts Ave., Cambridge, MA 02139.

³ To whom correspondence should be addressed. Fax: 530-752-3516; E-mail: jwhershey{at}ucdavis.edu.

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