Phosphorylated STAT5 regulates p53 expression via BRCA1/BARD1-NPM1 and MDM2

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 conne...

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Bibliographic Details
Published in:Cell death & disease 2016-12, Vol.7 (12), p.e2560-e2560
Main Authors: Ren, Zhuo, Aerts, Joeri L, Vandenplas, Hugo, Wang, Jiance A, Gorbenko, Olena, Chen, Jack P, Giron, Philippe, Heirman, Carlo, Goyvaerts, Cleo, Zacksenhaus, Eldad, Minden, Mark D, Stambolic, Vuk, Breckpot, Karine, De Grève, Jacques
Format: Article
Language:English
Subjects:
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Antibodies
Biochemistry
Biomedical and Life Sciences
BRCA1 Protein - metabolism
Cell Biology
Cell Culture
Cell Line
Cell Survival
Down-Regulation
Gene expression
Gene Knockdown Techniques
Humans
Immunology
Life Sciences
Lymphoma
Models, Biological
Nuclear Proteins - metabolism
Original
original-article
Phosphorylation
Phosphotyrosine - metabolism
Protein Binding
Proteolysis
Proto-Oncogene Proteins c-mdm2 - metabolism
STAT5 Transcription Factor - metabolism
Studies
Tumor Suppressor Protein p53 - metabolism
Tumor Suppressor Proteins - metabolism
Ubiquitin-Protein Ligases - metabolism
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Summary: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.
ISSN:2041-4889
2041-4889
DOI:10.1038/cddis.2016.430