Translation initiation factor 4E inhibits differentiation of erythroid progenitors.
Stem cell factor (SCF) delays differentiation and enhances the expansion of erythroid progenitors. Previously, we performed expression-profiling experiments to link signaling pathways to target genes using polysome-bound mRNA. SCF-induced phosphoinositide-3-kinase (PI3K) appeared to control polysome recruitment of specific mRNAs associated with neoplastic transformation. To evaluate the role of mRNA translation in the regulation of expansion versus differentiation of erythroid progenitors, we examined the function of the eukaryote initiation factor 4E (eIF4E) in these cells. SCF induced a rapid and complete phosphorylation of eIF4E-binding protein (4E-BP). Overexpression of eIF4E did not induce factor-independent growth but specifically impaired differentiation into mature erythrocytes. Overexpression of eIF4E rendered polysome recruitment of mRNAs with structured 5' untranslated regions largely independent of growth factor and resistant to the PI3K inhibitor LY294002. In addition, overexpression of eIF4E rendered progenitors insensitive to the differentiation-inducing effect of LY294002, indicating that control of mRNA translation is a major pathway downstream of PI3K in the regulation of progenitor expansion.
Blázquez-Domingo
Montserrat
M
Department of Hematology, Erasmus Medical Center, PO Box 1738, 3000 DR Rotterdam, The Netherlands.
Grech
Godfrey
G
von Lindern
Marieke
M
D020121:5' Untranslated Regions; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D002867:Chromones / Q000494:pharmacology; D017931:DNA Primers / Q000737:chemistry; D018076:DNA, Complementary / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004912:Erythrocytes / Q000166:cytology*; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism / Q000502:physiology*; D005434:Flow Cytometry; D005822:Genetic Vectors; D006160:Guanosine Triphosphate / Q000737:chemistry; D006454:Hemoglobins / Q000378:metabolism; D047468:Immunoprecipitation; D051379:Mice; D008856:Microscopy, Fluorescence; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011132:Polyribosomes / Q000737:chemistry / Q000378:metabolism; D014176:Protein Biosynthesis; D012313:RNA / Q000737:chemistry; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012685:Sepharose / Q000737:chemistry; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology*; D013997:Time Factors
D020121:5' Untranslated Regions; D002867:Chromones; D017931:DNA Primers; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D039561:Eukaryotic Initiation Factor-4E; D006454:Hemoglobins; D009025:Morpholines; D012333:RNA, Messenger; D019089:Stem Cell Factor; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D012313:RNA; D006160:Guanosine Triphosphate; D012685:Sepharose; D019869:Phosphatidylinositol 3-Kinases