title: 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 S102mutations 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-1S102Denhanced proliferation implying that S102phosphorylation 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.
authors.affiliation: Department of Experimental Pediatrics, University Hospital, Otto-von-Guericke University, Magdeburg 39120, Germany.
authors.forename: Steffi
authors.initials: S
authors.lastname: Gieseler-Halbach
authors.affiliation: Department of Experimental Pediatrics, University Hospital, Otto-von-Guericke University, Magdeburg 39120, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Meltendorf
authors.affiliation: Department of Experimental Pediatrics, University Hospital, Otto-von-Guericke University, Magdeburg 39120, Germany.
authors.forename: Mandy
authors.initials: M
authors.lastname: Pierau
authors.affiliation: Department of Internal Medicine, Division of Cardiology and Angiology, University Hospital, Otto-von-Guericke University, Magdeburg 39120, Germany.
authors.forename: Soenke
authors.initials: S
authors.lastname: Weinert
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, University Hospital, Otto-von-Guericke University, Magdeburg 39120, Germany.|Internal Medicine II, Hematology and Oncology, Medical Faculty, Friedrich-Schiller-University Jena, Leibniz-Institute on Aging, Fritz-Lipmann-Institute, Jena 07745, Germany.
authors.forename: Florian H
authors.initials: FH
authors.lastname: Heidel
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, University Hospital, Otto-von-Guericke University, Magdeburg 39120, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Fischer
authors.affiliation: Department of Neurochemistry and Molecular Biology, Leibniz Institute for Neurobiology, Magdeburg 39118, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Handschuh
authors.affiliation: Department of Internal Medicine, Division of Cardiology and Angiology, University Hospital, Otto-von-Guericke University, Magdeburg 39120, Germany.
authors.forename: Ruediger C
authors.initials: RC
authors.lastname: Braun-Dullaeus
authors.affiliation: Department of Pediatrics, University Medical Centre Schleswig-Holstein, Kiel, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schrappe
authors.affiliation: Clinic of Nephrology, Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University, Magdeburg 39120, Germany.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Lindquist
authors.affiliation: Clinic of Nephrology, Hypertension, Diabetes and Endocrinology, Otto-von-Guericke University, Magdeburg 39120, Germany.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Mertens
authors.affiliation: Department of Neurochemistry and Molecular Biology, Leibniz Institute for Neurobiology, Magdeburg 39118, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Thomas
authors.affiliation: Department of Experimental Pediatrics, University Hospital, Otto-von-Guericke University, Magdeburg 39120, Germany.
authors.forename: Monika C
authors.initials: MC
authors.lastname: Brunner-Weinzierl
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001578:Benzopyrans / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D004768:Enterotoxins / Q000633:toxicity; D005260:Female; D006801:Humans; D019169:Jurkat Cells; D008297:Male; D008875:Middle Aged; D009005:Monosaccharides / Q000494:pharmacology; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation / Q000187:drug effects; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D034622:RNA Interference; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051840:Y-Box-Binding Protein 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: D001578:Benzopyrans; D004768:Enterotoxins; D009005:Monosaccharides; C497449:SL0101; D051840:Y-Box-Binding Protein 1; D051057:Proto-Oncogene Proteins c-akt; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D011493:Protein Kinase C