title: Phosphorylated STAT5 regulates p53 expression via BRCA1/BARD1-NPM1 and MDM2.
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.
authors.affiliation: Laboratory of Medical and Molecular Oncology (LMMO), Department of Medical Oncology, Vrije Universiteit Brussel, Brussels, Belgium.|Department of General Surgery, The First People's Hospital of Shanghai, Shanghai Jiaotong University, Shanghai, China.|Department of Medical Oncology, Oncologisch Centrum of the Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium.|Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Ren
authors.affiliation: Laboratory of Molecular and Cellular Therapy, Department of Physiology and Immunology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Joeri L
authors.initials: JL
authors.lastname: Aerts
authors.affiliation: Laboratory of Medical and Molecular Oncology (LMMO), Department of Medical Oncology, Vrije Universiteit Brussel, Brussels, Belgium.|Department of Medical Oncology, Oncologisch Centrum of the Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Hugo
authors.initials: H
authors.lastname: Vandenplas
authors.affiliation: Department of Medicine and Medical Biophysics, University of Toronto, Toronto, ON, Canada.
authors.forename: Jiance A
authors.initials: JA
authors.lastname: Wang
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Olena
authors.initials: O
authors.lastname: Gorbenko
authors.affiliation: Department of Medicine and Medical Biophysics, University of Toronto, Toronto, ON, Canada.
authors.forename: Jack P
authors.initials: JP
authors.lastname: Chen
authors.affiliation: Laboratory of Medical and Molecular Oncology (LMMO), Department of Medical Oncology, Vrije Universiteit Brussel, Brussels, Belgium.|Department of Medical Oncology, Oncologisch Centrum of the Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Philippe
authors.initials: P
authors.lastname: Giron
authors.affiliation: Laboratory of Molecular and Cellular Therapy, Department of Physiology and Immunology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Carlo
authors.initials: C
authors.lastname: Heirman
authors.affiliation: Laboratory of Molecular and Cellular Therapy, Department of Physiology and Immunology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Cleo
authors.initials: C
authors.lastname: Goyvaerts
authors.affiliation: Department of Medicine and Medical Biophysics, University of Toronto, Toronto, ON, Canada.|Toronto General Research Institute, University Health Network, Toronto, ON, Canada.
authors.forename: Eldad
authors.initials: E
authors.lastname: Zacksenhaus
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.|Department of Medicine and Medical Biophysics, University of Toronto, Toronto, ON, Canada.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Minden
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.|Department of Medicine and Medical Biophysics, University of Toronto, Toronto, ON, Canada.
authors.forename: Vuk
authors.initials: V
authors.lastname: Stambolic
authors.affiliation: Laboratory of Molecular and Cellular Therapy, Department of Physiology and Immunology, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Karine
authors.initials: K
authors.lastname: Breckpot
authors.affiliation: Laboratory of Medical and Molecular Oncology (LMMO), Department of Medical Oncology, Vrije Universiteit Brussel, Brussels, Belgium.|Department of Medical Oncology, Oncologisch Centrum of the Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Jacques
authors.initials: J
authors.lastname: De Grève
mesh_terms: D019313:BRCA1 Protein / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival; D015536:Down-Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D008954:Models, Biological; D009687:Nuclear Proteins / Q000378:metabolism*; D000090243:Nucleophosmin; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011485:Protein Binding; D059748:Proteolysis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D000090243:Nucleophosmin; D019000:Phosphotyrosine; C102449:BARD1 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases