title: Casein kinase 1ε promotes cell proliferation by regulating mRNA translation.
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.
authors.affiliation: 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.
authors.forename: Sejeong
authors.initials: S
authors.lastname: Shin
authors.forename: Laura
authors.initials: L
authors.lastname: Wolgamott
authors.forename: Philippe P
authors.initials: PP
authors.lastname: Roux
authors.forename: Sang-Oh
authors.initials: SO
authors.lastname: Yoon
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D048149:Casein Kinase 1 epsilon / Q000378:metabolism*; D018797:Cell Cycle Proteins; D016923:Cell Death / Q000235:genetics / Q000502:physiology; D048708:Cell Growth Processes / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D039642:Eukaryotic Initiation Factors; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; C499527:Eif4ebp1 protein, mouse; D039642:Eukaryotic Initiation Factors; D010750:Phosphoproteins; D012333:RNA, Messenger; D048149:Casein Kinase 1 epsilon