E3, a hematopoietic-specific transcript directly regulated by the retinoic acid receptor alpha.
Retinoic acid (RA)-induced maturation mediated by the retinoic acid receptor alpha (RAR alpha) has been implicated in myeloid development. We have used differential hybridization analysis of a cDNA library constructed from the murine RA-inducible MPRO promyelocyte cell line to identify immediate-early genes induced by RA during granulocytic differentiation. E3, one of nine sequences identified, was upregulated in an immediate-early manner, with transcript levels peaking after 60 minutes exposure to RA. E3 transcripts were RA-inducible in HL60 cells, but not in an RA-resistant subclone, HL60R, that harbors a mutated RAR alpha gene. However, when HL60R cells were transduced with a functional copy of the RAR alpha gene, RA induced a 10-fold increase in E3 mRNA levels. E3 transcripts are present in the myeloid, B-lymphoid, and erythroid lineages, absent in nonhematopoietic cells, and encode a highly hydrophobic, potentially phosphorylated polypeptide of unknown function with significant homology to a putative protein expressed in myeloid cells. The murine E3 promoter harbors a single bipartite retinoic acid response element which in transient transfection assays conferred RA sensitivity. These results indicate that E3 is a hematopoietic-specific gene that is an immediate target for the activated RAR alpha during myelopoiesis.
Scott
L M
LM
Division of Molecular Medicine, Fred Hutchinson Cancer Research Center, Seattle, WA 98104, USA.
Mueller
L
L
Collins
S J
SJ
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation; D002478:Cells, Cultured; D016384:Consensus Sequence; D018076:DNA, Complementary / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects*; D017781:Genes, Immediate-Early; D006098:Granulocytes / Q000166:cytology; D018922:HL-60 Cells / Q000187:drug effects / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D015473:Leukemia, Promyelocytic, Acute / Q000473:pathology; D008565:Membrane Proteins; D051379:Mice; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000473:pathology; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000502:physiology*; D012045:Regulatory Sequences, Nucleic Acid; D000072482:Retinoic Acid Receptor alpha; D012689:Sequence Homology, Nucleic Acid; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology*
D018076:DNA, Complementary; D017874:Immediate-Early Proteins; C484408:Laptm5 protein, mouse; D008565:Membrane Proteins; C000607071:RARA protein, human; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin