AUF-1 and YB-1 are critical determinants of beta-globin mRNA expression in erythroid cells.

摘要

The normal accumulation of beta-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 beta-globin mRNA within the nucleus of early erythroid progenitors are unlikely to account for the constitutively high half-life of beta-globin mRNA in the cytoplasm of their anucleate erythroid progeny. We conducted in vitro protein-RNA binding analyses that identified a cytoplasm-restricted beta-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 beta-globin 3'untranslated region that has recently been implicated as a determinant of beta-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 beta-globin mRNA in erythroid precursors. These data define a previously unrecognized mechanism for the posttranscriptional regulation of beta-globin mRNA during normal erythropoiesis, providing new therapeutic targets for disorders of beta-globin gene expression.