title: Mitotic protein kinase CDK1 phosphorylation of mRNA translation regulator 4E-BP1 Ser83 may contribute to cell transformation.
abstract: Mammalian target of rapamycin (mTOR)-directed eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) phosphorylation promotes cap-dependent translation and tumorigenesis. During mitosis, cyclin-dependent kinase 1 (CDK1) substitutes for mTOR and fully phosphorylates 4E-BP1 at canonical sites (T37, T46, S65, and T70) and the noncanonical S83 site, resulting in a mitosis-specific hyperphosphorylated δ isoform. Colocalization studies with a phospho-S83 specific antibody indicate that 4E-BP1 S83 phosphorylation accumulates at centrosomes during prophase, peaks at metaphase, and decreases through telophase. Although S83 phosphorylation of 4E-BP1 does not affect general cap-dependent translation, expression of an alanine substitution mutant 4E-BP1.S83A partially reverses rodent cell transformation induced by Merkel cell polyomavirus small T antigen viral oncoprotein. In contrast to inhibitory mTOR 4E-BP1 phosphorylation, these findings suggest that mitotic CDK1-directed phosphorylation of δ-4E-BP1 may yield a gain of function, distinct from translation regulation, that may be important in tumorigenesis and mitotic centrosome function.
authors.affiliation: Cancer Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213;
authors.forename: Celestino
authors.initials: C
authors.lastname: Velásquez
authors.affiliation: Cancer Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213;
authors.forename: Erdong
authors.initials: E
authors.lastname: Cheng
authors.affiliation: Cancer Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213;
authors.forename: Masahiro
authors.initials: M
authors.lastname: Shuda
authors.affiliation: Cancer Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213;
authors.forename: Paula J
authors.initials: PJ
authors.lastname: Lee-Oesterreich
authors.affiliation: Cancer Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213;
authors.forename: Lisa
authors.initials: L
authors.lastname: Pogge von Strandmann
authors.affiliation: Biological Sciences Division/Biological Systems Analysis & Mass Spectrometry, Pacific Northwest National Laboratory, Richland, WA 99352.
authors.forename: Marina A
authors.initials: MA
authors.lastname: Gritsenko
authors.affiliation: Biological Sciences Division/Biological Systems Analysis & Mass Spectrometry, Pacific Northwest National Laboratory, Richland, WA 99352.
authors.forename: Jon M
authors.initials: JM
authors.lastname: Jacobs
authors.affiliation: Cancer Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213; yc70@pitt.edu psm9@pitt.edu.
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Moore
authors.affiliation: Cancer Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213; yc70@pitt.edu psm9@pitt.edu.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002460:Cell Line; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D018385:Centrosome / Q000378:metabolism; D045325:HCT116 Cells; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008938:Mitosis / Q000235:genetics; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics; D012694:Serine / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D010750:Phosphoproteins; D012333:RNA, Messenger; D012694:Serine; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human
keywords: 4E-BP; Merkel cell polyomavirus; cap-dependent translation; cyclin-dependent kinase 1; mitosis