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Decreased expression of eukaryotic initiation factor 3f deregulates translation and apoptosis in tumor cells

Oncogene volume 25, pages 4923–4936 (2006)Cite this article

Abstract

The eukaryotic initiation factor 3f (eIF3f) is the p47 subunit of the multi-subunit eIF3 complex. eIF3 plays an important role in translation initiation. In the present study, we investigate the biological function of eIF3f in translation and apoptosis in tumor cells. We demonstrated for the first time that eIF3f is downregulated in most human tumors using a cancer profiling array and confirmed by real-time reverse transcription PCR in melanoma and pancreatic cancer. Overexpression of eIF3f inhibits cell proliferation and induces apoptosis in melanoma and pancreatic cancer cells. Silencing of eIF3f protects melanoma cells from apoptosis. We further investigated the biological function of eIF3f. In vitro translation studies indicate that eIF3f is a negative regulator of translation and that the region between amino acids 170 and 248 of eIF3f is required for its translation regulatory function. Ectopic expression of eIF3f inhibits translation and overall cellular protein synthesis. Ribosome profile and ribosomal RNA (rRNA) fragmentation assays revealed that eIF3f reduces ribosomes, which may be associated with rRNA degradation. We propose that eIF3f may play a role in ribosome degradation during apoptosis. These data provide critical insights into the cellular function of eIF3f and in linking translation initiation and apoptosis.

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Abbreviations

7-AAD:

7-aminoactinomycin D

CDK11:

cyclin-dependent kinase 11

C t :

threshold cycle

eIF3:

eukaryotic initiation factor 3

GAPDH:

glyceraldehyde-3-phosphate dehydrogenase

GST:

glutathione S-transferase

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Acknowledgements

We thank the flow cytometry core at the University of Arizona for the apoptosis assay. We also thank the GI SPORE tissue core (Katie Benson, John Cunningham and Achyut Bhattacharyya) for providing us the pancreatic cancer tissues. We thank Roy Parker for critical discussions. This work was supported by Cancer Biology Training Grant CA 09213 from the National Institute of Health, Faculty Small Grant Program (University of Arizona), ABRC grant (5-102), Grants CA70145 (MN) and GM22135 (JH) and Center Grants ES066694 and GI SPORE CA95060.

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Authors and Affiliations

  1. Department of Pathology, University of Arizona, Tucson, AZ, USA

    J Shi, A Kahle & M A Nelson

  2. Department of Biological Chemistry, School of Medicine, University of California, Davis, CA, USA

    J W B Hershey

  3. Northern Arizona University, South San Francisco Street, Flagstaff, AZ, USA

    B M Honchak

  4. Arizona Cancer Center, University of Arizona, Tucson, AZ, USA

    J A Warneke

  5. Department of Surgery, UCSF Medical Center at Mount Zion, University of California, San Francisco, CA, USA

    S P L Leong

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  1. J Shi
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Correspondence to M A Nelson.

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Shi, J., Kahle, A., Hershey, J. et al. Decreased expression of eukaryotic initiation factor 3f deregulates translation and apoptosis in tumor cells. Oncogene 25, 4923–4936 (2006). https://doi.org/10.1038/sj.onc.1209495

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