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Molecular and Cellular Biology, March 2005, p. 2095-2106, Vol. 25, No. 6
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.6.2095-2106.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Inhibition of Protein Synthesis by Y Box-Binding Protein 1 Blocks Oncogenic Cell Transformation{dagger}

Andreas G. Bader1* and Peter K. Vogt1

Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California1

Received 12 October 2004/ Returned for modification 16 November 2004/ Accepted 17 December 2004

The multifunctional Y box-binding protein 1 (YB-1) is transcriptionally repressed by the oncogenic phosphoinositide 3-kinase (PI3K) pathway (with P3K as an oncogenic homolog of the catalytic subunit) and, when reexpressed with the retroviral vector RCAS, interferes with P3K- and Akt-induced transformation of chicken embryo fibroblasts. Retrovirally expressed YB-1 binds to the cap of mRNAs and inhibits cap-dependent and cap-independent translation. To determine the requirements for the inhibitory role of YB-1 in P3K-induced transformation, we conducted a mutational analysis, measuring YB-1-induced interference with transformation, subcellular localization, cap binding, mRNA binding, homodimerization, and inhibition of translation. The results show that (i) interference with transformation requires RNA binding and a C-terminal domain that is distinct from the cytoplasmic retention domain, (ii) interference with transformation is tightly correlated with inhibition of translation, and (iii) masking of mRNAs by YB-1 is not sufficient to block transformation or to inhibit translation. We identified a noncanonical nuclear localization signal (NLS) in the C-terminal half of YB-1. A mutant lacking the NLS retains its ability to interfere with transformation, indicating that a nuclear function is not required. These results suggest that YB-1 interferes with P3K-induced transformation by a specific inhibition of translation through its RNA-binding domain and a region in the C-terminal domain. Potential functions of the C-terminal region are discussed.

* Corresponding author. Mailing address: The Scripps Research Institute, 10550 North Torrey Pines Rd., BCC239, La Jolla, CA 92037. Phone: (858) 784-9732. Fax: (858) 784-2070. E-mail: andreas{at}scripps.edu.

{dagger} This is manuscript no. 16934-MEM of The Scripps Research Institute.

Molecular and Cellular Biology, March 2005, p. 2095-2106, Vol. 25, No. 6
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.6.2095-2106.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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