PDGF2/c-sis mRNA Leader Contains a Differentiation-linked Internal Ribosomal Entry Site (D-IRES)

Abstract

It has become clear that a given cell type can qualitatively and quantitatively affect the expression of the platelet-derived growth factor B (PDGF2/c-sis) gene at multiple levels. In a previous report, we showed that PDGF2/c-sis 5'-untranslated region has a translational modulating activity during megakaryocytic differentiation of K562 cells. This study points to the mechanism used for this translational modulation. The unusual mRNA leader, which imposes a major barrier to conventional ribosomal scanning, was found to contain an internal ribosomal entry site that becomes more potent in differentiating cells and was termed differentiation-linked internal ribosomal entry site (D-IRES). The D-IRES element defines a functional role for the cumbersome 1022-nucleotide-long mRNA leader and accounts for its uncommon, evolutionary conserved architecture. The differentiation-linked enhancement of internal translation, which provides an additional step to the fine tuning of PDGF2/c-sis gene expression, might be employed by numerous critical regulatory genes with unusual mRNA leaders and might have widespread implications for cellular growth and development.