title: AUF-1 and YB-1 are critical determinants of β-globin mRNA expression in erythroid cells.
abstract: The normal accumulation of β-globin protein in terminally differentiating erythroid cells is critically dependent on the high stability of its encoding mRNA. The molecular basis for this property, though, is incompletely understood. Factors that regulate β-globin mRNA within the nucleus of early erythroid progenitors are unlikely to account for the constitutively high half-life of β-globin mRNA in the cytoplasm of their anucleate erythroid progeny. We conducted in vitro protein-RNA binding analyses that identified a cytoplasm-restricted β-globin messenger ribonucleoprotein (mRNP) complex in both cultured K562 cells and erythroid-differentiated human CD34(+) cells. This novel mRNP targets a specific guanine-rich pentanucleotide in a region of the β-globin 3'untranslated region that has recently been implicated as a determinant of β-globin mRNA stability. Subsequent affinity-enrichment analyses identified AUF-1 and YB-1, 2 cytoplasmic proteins with well-established roles in RNA biology, as trans-acting components of the mRNP. Factor-depletion studies conducted in vivo demonstrated the importance of the mRNP to normal steady-state levels of β-globin mRNA in erythroid precursors. These data define a previously unrecognized mechanism for the posttranscriptional regulation of β-globin mRNA during normal erythropoiesis, providing new therapeutic targets for disorders of β-globin gene expression.
authors: Department of Medicine (Hematology-Oncology), Perelman School of Medicine, University of Pennsylvania, and The Children’s Hospital of Philadelphia, 3615 Civic Center Blvd., Philadelphia, PA 19104, USA.
authors: Sebastiaan
authors: S
authors: van Zalen
authors: Grace R
authors: GR
authors: Jeschke
authors: Elizabeth O
authors: EO
authors: Hexner
authors: J Eric
authors: JE
authors: Russell
mesh_terms: D020413:3' Untranslated Regions; D018952:Antigens, CD34 / Q000378:metabolism; D002478:Cells, Cultured; D024202:Electrophoretic Mobility Shift Assay; D041905:Erythroid Cells / Q000378:metabolism*; D005312:Fetal Blood / Q000166:cytology; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006367:HeLa Cells; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D009154:Mutation; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism*; D034741:RNA, Small Interfering; D011994:Recombinant Proteins / Q000378:metabolism; D012261:Ribonucleoproteins / Q000378:metabolism; D051840:Y-Box-Binding Protein 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D055544:beta-Globins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D018952:Antigens, CD34; C000630986:HNRNPD protein, human; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D012261:Ribonucleoproteins; D051840:Y-Box-Binding Protein 1; C070856:YBX1 protein, human; D055544:beta-Globins