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Cancer Res. 2014 Jan 1;74(1):201-11. doi: 10.1158/0008-5472.CAN-13-1175. Epub 2013 Nov 18.

Casein kinase 1ε promotes cell proliferation by regulating mRNA translation.

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1
Authors' Affiliations: Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio; Department of Pathology and Cell Biology; and Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada.

Abstract

Deregulation of translation initiation factors contributes to many pathogenic conditions, including cancer. Here, we report the definition of a novel regulatory pathway for translational initiation with possible therapeutic import in cancer. Specifically, we found that casein kinase 1ε (CK1ε) is highly expressed in breast tumors and plays a critical role in cancer cell proliferation by controlling mRNA translation. Eukaryotic translation initiation factor eIF4E, an essential component of the translation initiation complex eIF4F, is downregulated by binding the negative-acting factor 4E-BP1. We found that genetic or pharmacologic inhibition of CK1ε attenuated 4E-BP1 phosphorylation, thereby increasing 4E-BP1 binding to eIF4E and inhibiting mRNA translation. Mechanistic investigations showed that CK1ε interacted with and phosphorylated 4E-BP1 at two novel sites T41 and T50, which were essential for 4E-BP1 inactivation along with increased mRNA translation and cell proliferation. In summary, our work identified CK1ε as a pivotal regulator of mRNA translation and cell proliferation that acts by inhibiting 4E-BP1 function. As CK1ε is highly expressed in breast tumors, these findings offer an initial rationale to explore CK1ε blockade as a therapeutic strategy to treat cancers driven by deregulated mRNA translation.

PMID:
24247720
DOI:
10.1158/0008-5472.CAN-13-1175
[Indexed for MEDLINE]
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