title: MicroRNA-34a perturbs B lymphocyte development by repressing the forkhead box transcription factor Foxp1.
abstract: MicroRNAs (miRNAs) can influence lineage choice or affect critical developmental checkpoints during hematopoiesis. We examined the role of the p53-induced microRNA miR-34a in hematopoiesis by gain-of-function analysis in murine bone marrow. Constitutive expression of miR-34a led to a block in B cell development at the pro-B-cell-to-pre-B-cell transition, leading to a reduction in mature B cells. This block appeared to be mediated primarily by inhibited expression of the transcription factor Foxp1. Foxp1 was a direct target of miR-34a in a 3'-untranslated region (UTR)-dependent fashion. Knockdown of Foxp1 by siRNA recapitulated the B cell developmental phenotype induced by miR-34a, whereas cotransduction of Foxp1 lacking its 3' UTR with miR-34a rescued B cell maturation. Knockdown of miR-34a resulted in increased amounts of Foxp1 and mature B cells. These findings identify a role for miR-34a in connecting the p53 network with suppression of Foxp1, a known B cell oncogene.
authors.affiliation: Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.
authors.forename: Dinesh S
authors.initials: DS
authors.lastname: Rao
authors.forename: Ryan M
authors.initials: RM
authors.lastname: O'Connell
authors.forename: Aadel A
authors.initials: AA
authors.lastname: Chaudhuri
authors.forename: Yvette
authors.initials: Y
authors.lastname: Garcia-Flores
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Geiger
authors.forename: David
authors.initials: D
authors.lastname: Baltimore
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D001853:Bone Marrow / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D003001:Cloning, Molecular; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006410:Hematopoiesis; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics; D054448:Precursor Cells, B-Lymphoid / Q000378:metabolism* / Q000473:pathology; D011828:Radiation Chimera; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; C486626:FOXP1 protein, human; D051858:Forkhead Transcription Factors; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53