Abstract
Signal transducer and activator of transcription 5 (STAT5) and nucleophosmin (NPM1) are critical regulators of multiple biological and pathological processes. Although a reciprocal regulatory relationship was established between STAT5A and a NPM–ALK fusion protein in T-cell lymphoma, no direct connection between STAT5 and wild-type NPM1 has been documented. Here we demonstrate a mutually regulatory relationship between STAT5 and NPM1. Induction of STAT5 phosphorylation at Y694 (P-STAT5) diminished NPM1 expression, whereas inhibition of STAT5 phosphorylation enhanced NPM1 expression. Conversely, NPM1 not only negatively regulated STAT5 phosphorylation but also preserved unphosphorylated STAT5 level. Mechanistically, we show that NPM1 downregulation by P-STAT5 is mediated by impairing the BRCA1-BARD1 ubiquitin ligase, which controls the stability of NPM1. In turn, decreased NPM1 levels led to suppression of p53 expression, resulting in enhanced cell survival. This study reveals a new STAT5 signaling pathway regulating p53 expression via NPM1 and uncovers new therapeutic targets for anticancer treatment in tumors driven by STAT5 signaling.
Highlights
Signal transducer and activator of transcription 5 (STAT5) is a prominent member of the STAT family, which exists in two highly homologous isoforms, STAT5A and STAT5B
To maintain persistent STAT5 phosphorylation, granulocyte macrophage colonystimulating factor (GM-CSF) is added to the culture medium of human erythroleukemic cell line TF-1.16 To investigate whether STAT5 phosphorylation at Y694 regulates NPM1 expression, we induced STAT5 phosphorylation by IL-3 stimulation in TF-1 cells deprived of GM-CSF and observed a significant downregulation of NPM1 coinciding with STAT5 phosphorylation at Y694 (P-STAT5, Figure 1a)
We demonstrate that P-STAT5-mediated downregulation of NPM1 expression is due to impaired ubiquitination by the BRCA1-BARD1 RING complex and that through the decrease of NPM P-STAT5 modulates p53 to execute its pro-survival effects (Figure 6a)
Summary
Signal transducer and activator of transcription 5 (STAT5) is a prominent member of the STAT family, which exists in two highly homologous isoforms, STAT5A and STAT5B. A reciprocally inhibitory relationship has been established between STAT5A and the tyrosine kinase NPM–ALK fusion protein in T-cell lymphoma.[5] Nucleophosmin (NPM1) is a phosphoprotein involved in many cellular processes, including cell cycle regulation, centrosome duplication and the formation of a complex network with apoptosis-related proteins, such as p53, MDM2 and Arf.[6] NPM1 can stabilize p53 through direct physical interaction by inhibiting MDM2-mediated p53 ubiquitination.[7,8] NPM1 has been identified as a substrate of BRCA1-BARD1 ubiquitin ligase, which results in its stabilization and localization in the centrosome during cell mitosis to guard against centrosome hyperamplification. STAT5 and NPM1 are functionally related as they are both involved in mediating certain biological activities and pathological processes Both STAT5 and NPM1 are key players in mediating the long-term self-renewal of human stem/progenitor cells.[10,11] STAT5 and NPM1 abnormalities were separately found in acute myeloid leukemia (AML). Our results provide novel mechanistic insights into STAT5- and NPM1mediated activities as well as potential new therapeutic targets
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