RSK-mediated nuclear accumulation of the cold-shock Y-box protein-1 controls proliferation of T cells and T-ALL blasts

Abstract

Deregulated proliferation is key to tumor progression. Although unrestricted proliferation of solid tumor cells correlates with the cold-shock protein Y-box (YB)-binding protein-1 accumulation in the nuclei, little is known about its expression and function in hematopoietic malignancies, such as T-cell acute lymphoblastic leukemia (T-ALL). Here we show that YB-1 protein is highly enriched in the nuclei of activated T cells and malignant human T-ALL cell lines but not in resting T cells. YB-1 S 102 mutations that either mimic (S102D) or prevent phosphorylation (S102N) led to accumulation of YB-1 in the nucleus of T cells or strictly excluded it, respectively. Inactivation of ribosomal S6 kinase (RSK) was sufficient to abrogate T-cell and T-ALL cell proliferation, suggesting that RSK mediates cell-cycle progression, possibly dependent on YB-1-phosphorylation. Indeed, phosphomimetic YB-1 S102D enhanced proliferation implying that S 102 phosphorylation is a prerequisite for malignant T-cell proliferation. At initial diagnosis of T-ALL, YB-1 localization was significantly altered in the nuclei of tumor blasts derived from bone marrow or peripheral blood. Our data show deregulated YB-1 in the nucleus as a yet unreported characteristic of T-ALL blasts and may refine strategies to restrict progression of hematopoietic tumors.

Cold shock proteins: from cellular mechanisms to pathophysiology and disease

“…However, an inhibition of p70S6K, a member of the ribosomal S6 kinase (RSK) family, has also been reported [ 179 ]. Molecular modeling proposed that fisetin binds to the CSD of YB-1; if such binding prevents YB-1 from being phosphorylated then this proposal would unify these reports, as both kinases phosphorylate Ser 102 [ 144 , 180 , 181 ]. Regardless of the mechanism of action, fisetin prevents the nuclear translocation of YB-1 by preventing phosphorylation of the CSD.…”

YB-1 Interferes with TNFα–TNFR Binding and Modulates Progranulin-Mediated Inhibition of TNFα Signaling

“…Recently, we identified YB-1 as an essential component of the TNFR signaling cascade leading to NF-κB activation, as TNF stimulation of YB-1-deficient cells failed to activate NF-κB, as was previously shown for both IGF-1 and IL-1β signaling [ 58 , 59 , 60 ]. A failure to activate YB-1 and thus NF-κB, negatively impacts on cell survival in monocytes, macrophages, and T cells [ 60 , 61 , 62 ].…”

Fisetin targets YB-1/RSK axis independent of its effect on ERK signaling: insights from in vitro and in vivo melanoma models

“…We postulate formation of a ‘ternary complex’ between RSK2/YB-1/fisetin, where fisetin stabilizes the interaction between RSK2 and YB-1 by acting at the interface between the two kinases. The interaction between RSK and YB-1 reportedly culminates in phosphorylation and activation of YB-1 24 , 39 . In our model, however, binding of RSK2 with YB-1 does not translate into increased activity of YB-1.…”