Translational control of putative protooncogene Nm23-M2 by cytokines via phosphoinositide 3-kinase signaling.
The expansion and differentiation of hematopoietic progenitors is regulated by cytokine and growth factor signaling. To examine how signal transduction controls the gene expression program required for progenitor expansion, we screened ATLAS filters with polysome-associated mRNA derived from erythroid progenitors stimulated with erythropoietin and/or stem cell factor. The putative proto-oncogene nucleoside diphosphate kinase B (ndpk-B or nm23-M2) was identified as an erythropoietin and stem cell factor target gene. Factor-induced expression of nm23-M2 was regulated specifically at the level of polysome association by a phosphoinositide 3-kinase-dependent mechanism. Identification of the transcription initiation site revealed that nm23-M2 mRNA starts with a terminal oligopyrimidine sequence, which is known to render mRNA translation dependent on mitogenic factors. Recently, the nm23-M2 locus was identified as a common leukemia retrovirus integration site, suggesting that it plays a role in leukemia development. The expression of Nm23 from a retroviral vector in the absence of its 5'-untranslated region caused constitutive polysome association of nm23-M2. Polysome-association and protein expression of endogenous nm23-M2 declined during differentiation of erythroid progenitors, suggesting a role for Nm23-M2 in progenitor expansion. Taken together, nm23-m2 exemplifies that cytokine-dependent control of translation initiation is an important mechanism of gene expression regulation.
Joosten
Marieke
M
Department of Hematology, Erasmus Medical Center, P. O. Box 1738, 3000 DR Rotterdam, The Netherlands.
Blázquez-Domingo
Montserrat
M
Lindeboom
Fokke
F
Boulmé
Florence
F
Van Hoven-Beijen
Antoinette
A
Habermann
Bianca
B
Löwenberg
Bob
B
Beug
Hartmut
H
Müllner
Ernst W
EW
Delwel
Ruud
R
Von Lindern
Marieke
M
D020121:5' Untranslated Regions; D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D002454:Cell Differentiation; D002478:Cells, Cultured; D003001:Cloning, Molecular; D017931:DNA Primers / Q000737:chemistry; D018076:DNA, Complementary / Q000378:metabolism; D015536:Down-Regulation; D004921:Erythropoietin / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation; D015971:Gene Expression Regulation, Enzymologic; D005822:Genetic Vectors; D051379:Mice; D008969:Molecular Sequence Data; D054778:NM23 Nucleoside Diphosphate Kinases; D009690:Nucleic Acid Conformation; D009701:Nucleoside-Diphosphate Kinase / Q000235:genetics* / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011061:Poly A / Q000378:metabolism; D011132:Polyribosomes / Q000378:metabolism; D014176:Protein Biosynthesis; D011743:Pyrimidines / Q000737:chemistry; D012333:RNA, Messenger / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation
D020121:5' Untranslated Regions; D017931:DNA Primers; D018076:DNA, Complementary; D054778:NM23 Nucleoside Diphosphate Kinases; D011743:Pyrimidines; D012333:RNA, Messenger; D019089:Stem Cell Factor; D004921:Erythropoietin; D011061:Poly A; D019869:Phosphatidylinositol 3-Kinases; C517939:Nme1 protein, mouse; C517941:Nme2 protein, mouse; D009701:Nucleoside-Diphosphate Kinase