Interplay between Y-box-binding protein 1 (YB-1) and poly(A) binding protein (PABP) in specific regulation ofYB-1mRNA translation

Abstract

YB-1 is a DNA- and RNA-binding protein that regulates expression of many important genes. Its deficiency or excess may pose threats, including malignant cellular transformation and metastasis, which explains the necessity of strict control over its amount at every level. As we showed previously, the 3' untranslated region (UTR) of YB-1 mRNA contains a regulatory element specifically binding to YB-1 and PABP (PABPC1). Also, we showed that YB-1 selectively inhibits YB-1 mRNA translation, while PABP stimulates it in a poly(A) tail-independent manner. It was suggested that regulation of YB-1 mRNA translation involves competition between PABP and YB-1 for binding to the regulatory element. Here we offer cogent evidence for this model and add novel details to the mechanism of regulation of YB-1 synthesis. In experiments on regulatory element deletion we showed that it is this element that is responsible for a specific effect of YB-1 and PABP on YB-1 mRNA translation. Mutations eliminating only specific YB-1 affinity for this element suppressed the inhibitory effect of YB-1 and concurrently dramatically decreased the PABP stimulating effect. Mutations reducing only specific PABP affinity for this element, as well as spatial separation of the YB-1- and PABP binding sites, did not affect the YB-1 inhibitory action but completely abolished the positive PABP effect. Together, these results unambiguously prove direct inhibitory action of YB-1 on its mRNA translation, while the positive effect of PABP is realized through displacing YB-1 from the regulatory element.

Specific PABP effect on translation ofYB-1mRNA is neutralized by polyadenylation through a “mini-loop” at 3′ UTR

“…YB-1-to-RE binding results in inhibition of translation either at the step of mRNA joining to the 43S preinitiation complex or at the previous step of mRNA interaction with translation initiation factors, 23,24 while PABP-to-RE binding causes YB-1 displacement, and hence, activation of translation of YB-1 mRNA. 22,24 It should be noted that the above studies used poly A(-) YB-1 mRNA and revealed only the results of PABP interaction with 3' UTR lacking the poly(A) tail. The current study shows that polyadenylation of YB-1 mRNA stimulates its translation in rabbit reticulocyte lysate (RRL).…”

Novel Potent and Selective Inhibitors of p90 Ribosomal S6 Kinase Reveal the Heterogeneity of RSK Function in MAPK-Driven Cancers

“…YB1 regulates transcription and translation by binding to its recognition motifs in both DNA and RNA to regulate key cell processes such as proliferation, motility, and stemness characteristics (6)(7)(8)(9)(10)(11). Two kinases, RSK and AKT, have been studied as regulators of YB1 function through phosphorylation of YB1 on Serine 102 (12,13).…”

MYC-Induced Epigenetic Activation of GATA4 in Lung Adenocarcinoma

“…A Y-box sequence is located directly downstream. The Y-box-binding protein 1 regulates the expression of many important genes (24) and is involved in the development of metastasis in patients with gastric and breast cancer (25). This protein may bind to the hypomethylated region of the GATA4 promoter, and thus regulate its expression, or even act as a partner in metastasis development.…”