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: Sejeong Shin, Laura Wolgamott, Philippe P Roux, Sang-Oh Yoon
• Journal: Cancer research (Cancer Res) Vol. 74 Issue 1 Pg. 201-11 (Jan 01 2014) ISSN: 1538-7445 [Electronic] United States
• PMID: 24247720 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Carrier Proteins
• Cell Cycle Proteins
• EIF4EBP1 protein, human
• Eif4ebp1 protein, mouse
• Eukaryotic Initiation Factors
• Phosphoproteins
• RNA, Messenger
• Casein Kinase 1 epsilon

Topics

• Adaptor Proteins, Signal Transducing (genetics, metabolism)
• Animals
• Breast Neoplasms (enzymology, genetics, immunology, pathology)
• Carrier Proteins (genetics, metabolism)
• Casein Kinase 1 epsilon (metabolism)
• Cell Cycle Proteins
• Cell Death (genetics, physiology)
• Cell Growth Processes (genetics, physiology)
• Cell Line, Tumor
• Eukaryotic Initiation Factors
• Female
• HEK293 Cells
• Humans
• Mice
• Mice, Nude
• Phosphoproteins (genetics, metabolism)
• Phosphorylation
• RNA, Messenger (genetics, metabolism)