Inhibition of Transcription Induces Phosphorylation of YB-1 at Ser102 and Its Accumulation in the Nucleus

Abstract

The Y-box binding protein 1 (YB-1) is an RNA/DNA-binding protein regulating gene expression in the cytoplasm and the nucleus. Although mostly cytoplasmic, YB-1 accumulates in the nucleus under stress conditions. Its nuclear localization is associated with aggressiveness and multidrug resistance of cancer cells, which makes the understanding of the regulatory mechanisms of YB-1 subcellular distribution essential. Here, we report that inhibition of RNA polymerase II (RNAPII) activity results in the nuclear accumulation of YB-1 accompanied by its phosphorylation at Ser102. The inhibition of kinase activity reduces YB-1 phosphorylation and its accumulation in the nucleus. The presence of RNA in the nucleus is shown to be required for the nuclear retention of YB-1. Thus, the subcellular localization of YB-1 depends on its post-translational modifications (PTMs) and intracellular RNA distribution.

Y-Box Binding Proteins in mRNP Assembly, Translation, and Stability Control

“…Possibly, YB-1 binds mRNAs immediately after or co-transcriptionally, and its translocation to the cytoplasm occurs in concert with mRNAs and mediates by RNA export proteins. This hypothesis is indirectly supported by two facts: fast YB-1 export after the cessation of the transcription blockage [211] and YB-1 association with chromatin [89,90] suggesting co-transcriptional YB-1 binding to nascent RNA.…”

“…It is unknown how mutations in RNP consensuses influence the CSD structure and stability; therefore, it is difficult to conclude whether the CSD itself or its RNA-binding ability is responsible for YB-1 retention in the cytoplasm. It is a recent finding that long-lasting transcription inhibition causes mRNA degradation and promotes YB-1 accumulation in the nucleus [211][212][213][214]. Of note, upon transcription inhibition, not only the cytoplasmic mRNA content but also YB-1 modifications play a key role in the YB-1 nuclear import [211].…”

“…It is a recent finding that long-lasting transcription inhibition causes mRNA degradation and promotes YB-1 accumulation in the nucleus [211][212][213][214]. Of note, upon transcription inhibition, not only the cytoplasmic mRNA content but also YB-1 modifications play a key role in the YB-1 nuclear import [211]. The best-studied YB-1 modification is its phosphorylation at Ser102 by Akt or RSK [75,161,162], which promotes YB-1 nuclear accumulation [159][160][161] by an unknown mechanism.…”

Long non-coding RNA MIR200CHG promotes breast cancer proliferation, invasion, and drug resistance by interacting with and stabilizing YB-1

“…When cells undergo environmental stimulation, YB-1 is affected by the PI3K/Akt and MAPK/ERK signaling pathways, and the serine residue 102 on its CSD is phosphorylated, which promotes nuclear translocation 25,26 . Ser102 phosphorylation not only helps YB-1 as a transcription factor to activate or inhibit the expression of related genes, but also helps YB-1 to participate in the DNA repair process 27 . Our study confirms that MIR200CHG is involved in the phosphorylation regulation of YB-1 serine 102, but it is not clear how MIR200CHG activates YB-1 phosphorylation.…”

YB-1 Oncoprotein Controls PI3K/Akt Pathway by Reducing Pten Protein Level

“…The nuclear accumulation of YB-1 in response to DNA damage or transcription inhibition requires a decrease in the cytoplasmic mRNA level [11]. Indeed, like Akt, YB-1 is associated with inactive mRNPs and, activated Akt relieves translational repression of the YB-1-bound mRNAs thereby facilitating translational activation of silenced mRNA species [3,12].…”