title: Dok1 and Dok2 Proteins Regulate Cell Cycle in Hematopoietic Stem and Progenitor Cells.
abstract: Dok1 and Dok2 proteins play a crucial role in myeloid cell proliferation as demonstrated by Dok1 and Dok2 gene inactivation, which induces a myeloproliferative disease in aging mice. In this study, we show that Dok1/Dok2 deficiency affects myeloproliferation even at a young age. An increase in the cellularity of multipotent progenitors is observed in young Dok1/Dok2-deficient mice. This is associated with an increase in the cells undergoing cell cycle, which is restricted to myeloid committed progenitors. Furthermore, cellular stress triggered by 5-fluorouracil (5-FU) treatment potentiates the effects of the loss of Dok proteins on multipotent progenitor cell cycle. In addition, Dok1/Dok2 deficiency induces resistance to 5-FU-induced hematopoietic stem cell exhaustion. Taken together, these results demonstrate that Dok1 and Dok2 proteins are involved in the control of hematopoietic stem cell cycle regulation.
authors.affiliation: INSERM, U1068, Centre de Recherche en Cancérologie de Marseille, 13009 Marseille, France; Institut Paoli-Calmettes, 13009 Marseille, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7258, Centre de Recherche en Cancérologie de Marseille, 13009 Marseille, France; Université d'Aix-Marseille, UM105, 13009 Marseille, France; coppine@pitt.edu jacques.nunes@inserm.fr.
authors.forename: Emilie
authors.initials: E
authors.lastname: Coppin
authors.affiliation: INSERM, U1068, Centre de Recherche en Cancérologie de Marseille, 13009 Marseille, France; Institut Paoli-Calmettes, 13009 Marseille, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7258, Centre de Recherche en Cancérologie de Marseille, 13009 Marseille, France; Université d'Aix-Marseille, UM105, 13009 Marseille, France;
authors.forename: Maria
authors.identifier: 0000-0001-6465-8723
authors.initials: M
authors.lastname: De Grandis
authors.affiliation: Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, MA 02215; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215; and Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
authors.affiliation: INSERM, U1068, Centre de Recherche en Cancérologie de Marseille, 13009 Marseille, France; Institut Paoli-Calmettes, 13009 Marseille, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7258, Centre de Recherche en Cancérologie de Marseille, 13009 Marseille, France; Université d'Aix-Marseille, UM105, 13009 Marseille, France;
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Arcangeli
authors.affiliation: INSERM, U1068, Centre de Recherche en Cancérologie de Marseille, 13009 Marseille, France; Institut Paoli-Calmettes, 13009 Marseille, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7258, Centre de Recherche en Cancérologie de Marseille, 13009 Marseille, France; Université d'Aix-Marseille, UM105, 13009 Marseille, France;
authors.forename: Michel
authors.identifier: 0000-0002-8361-3034
authors.initials: M
authors.lastname: Aurrand-Lions
authors.affiliation: INSERM, U1068, Centre de Recherche en Cancérologie de Marseille, 13009 Marseille, France; Institut Paoli-Calmettes, 13009 Marseille, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7258, Centre de Recherche en Cancérologie de Marseille, 13009 Marseille, France; Université d'Aix-Marseille, UM105, 13009 Marseille, France; coppine@pitt.edu jacques.nunes@inserm.fr.
authors.forename: Jacques A
authors.initials: JA
authors.lastname: Nunès
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002453:Cell Cycle; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D004249:DNA Damage / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005472:Fluorouracil / Q000633:toxicity; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000502:physiology*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C489561:Dok1 protein, mouse; C498444:Dok2 protein, mouse; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D005472:Fluorouracil