Identification of a novel and myeloid specific role of the leukemia-associated fusion protein DEK-NUP214 leading to increased protein synthesis.
The t(6;9)(p22;q34) chromosomal translocation is found in a subset of patients with acute myeloid leukemia (AML). The translocation results in a fusion between the nuclear phosphoprotein DEK and the nucleoporin NUP214 (previously CAN). The mechanism by which the fusion protein DEK-NUP214 contributes to leukemia development has not been identified, and disruptions of normal cellular functions by DEK-NUP214 have previously not been described. In the present study, a novel effect of the DEK-NUP214 fusion protein is demonstrated. Our findings reveal a substantial increase in global protein synthesis in DEK-NUP214 expressing cells. Furthermore, we conclude that this effect is not the result of dysregulated transcription but merely due to increased translation. Consistent with the association with AML, the increased protein synthesis mediated by DEK-NUP214 is restricted to cells of the myeloid lineage. Analysis of potential mechanisms for regulating protein synthesis shows that expression of DEK-NUP214 correlates to the phosphorylation of the translation initiation protein, EIF4E. The present data provide evidence that increase of translational activity constitutes a mechanism by which the leukemogenic effect of DEK-NUP124 may be mediated.
Ageberg
Malin
M
Division of Hematology and Transfusion Medicine, Faculty of Medicine, Lund University, Lund, Sweden. Malin.Ageberg@med.lu.se
Drott
Kristina
K
Olofsson
Tor
T
Gullberg
Urban
U
Lindmark
Anders
A
D017209:Apoptosis; D015153:Blotting, Western; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D005434:Flow Cytometry; D015973:Gene Expression Regulation, Leukemic / Q000502:physiology; D017930:Genes, Reporter; D005822:Genetic Vectors; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism*; D008156:Luciferases / Q000378:metabolism; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D015514:Oncogene Proteins, Fusion / Q000502:physiology*; D010766:Phosphorylation; D014176:Protein Biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured
C104001:DEK-CAN fusion protein, recombinant; D039561:Eukaryotic Initiation Factor-4E; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D008156:Luciferases