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Role of eIF3 p170 in controlling synthesis of ribonucleotide reductase M2 and cell growth

Oncogene volume 23, pages 3790–3801 (2004)Cite this article

Abstract

Translation initiation in eukaryotes is a rate-limiting step in protein synthesis. It is a complicated process that involves many eukaryotic initiation factors (eIFs). Altering the expression level or the function of eIFs may influence the synthesis of some proteins and consequently cause abnormal cell growth and malignant transformation. P170, the largest putative subunit of eIF3, has been found elevated in human breast, cervical, esophageal, and lung cancers, suggesting that p170 may have a potential role in malignant transformation and/or cell growth control. Our recent studies suggested that p170 is likely a translational regulator and it may mediate the effect of mimosine on the translation of a subset mRNAs. Mimosine, a plant nonprotein amino acid, inhibits mammalian DNA synthesis, an essential event of cell growth. The rate-limiting step in DNA synthesis is the conversion of the ribonucleotides to their corresponding deoxyribonucleotides catalysed by ribonucleotide reductase of which the activity is regulated by the level of its M2 subunit. It has been reported that inhibiting the activity of M2 also inhibits cell growth. To understand the relationship between protein and DNA synthesis and between p170 and cell growth control, we investigated in this study whether p170 regulates the synthesis of M2 and, thus, cell growth. We found that altering the expression level of p170 changes the synthesis rate of both M2 and DNA. Decreasing p170 expression in human lung cancer cell line H1299 and breast cancer cell line MCF7 significantly reversed their malignant growth phenotype. However, the overall [35S]methionine incorporation following dramatic decrease in p170 expression was only ∼25% less than the control cells. These observations, together with our previous findings, suggest that p170 may regulate the translation of a subset mRNAs and its elevated expression level may be important for cancer cell growth and for maintaining their malignant phenotype.

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Acknowledgements

Technical assistance from Mr Min Choi is appreciated. Critical comments on an earlier version of this manuscript from Drs David Ohannesian and Martin Smith are also greatly appreciated. We also would like to thank Drs Keith R Johnson, Tang K Tang, Max M Burger, and Andrew Koff for their generosity in providing the necessary materials for this study. This work was supported by National Institutes of Health Grants (CA64539, GM59475, and CA94961) and Department of Defense Grant (DAMD170010297). J-TZ was a recipient of a Career Investigator Award from the American Lung Association.

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  1. Department of Pharmacology and Toxicology, Indiana University Cancer Center, Walther Oncology Center/Walther Cancer Institute, Indiana University School of Medicine, R4-166, 1044 W. Walnut Street, Indianapolis, 46202, IN, USA

    Zizheng Dong, Lisa H Liu, Baoguang Han, Roxana Pincheira & Jian-Ting Zhang

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  1. Zizheng Dong
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Correspondence to Jian-Ting Zhang.

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Dong, Z., Liu, L., Han, B. et al. Role of eIF3 p170 in controlling synthesis of ribonucleotide reductase M2 and cell growth. Oncogene 23, 3790–3801 (2004). https://doi.org/10.1038/sj.onc.1207465

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