title: Cks1 is a critical regulator of hematopoietic stem cell quiescence and cycling, operating upstream of Cdk inhibitors.
abstract: Cyclin-dependent kinase subunit 1 (Cks1) is a critical rate-limiting component of the Skp1-Cullin1-Skp2 (SCF(Skp2)) ubiquitin ligase that controls cell cycle inhibitor abundance. Cyclin-dependent kinase (Cdk) inhibitors (CKIs) regulate hematopoietic stem cell (HSC) self-renewal, regeneration after cytotoxic stress and tumor cell proliferation. We thus studied the role of Cks1 in HSC and in a prototypic stem cell disorder, chronic myeloid leukemia (CML). Cks1 transcript was highly expressed in Lin-Sca-1+Kit+ (LSK) HSC, and the loss resulted in accumulation of the SCF(Skp2)/Cks1 substrates p21, p27, p57 and p130 particularly in CD150+ LSK cells. This accumulation correlated with decreased proliferation and accumulation of Cks1(-/-) HSC, slower regeneration after stress and prolonged HSC quiescence. At the hematopoietic progenitor (HPC) level, loss of Cks1 sensitized towards apoptosis. In CML, Cks1 expression was increased, and treatment with the Abl kinase inhibitor, imatinib, reduced Cks1 expression. Also, we found that Cks1 is critical for Bcr-Abl-induced cytokine-independent clonogenic activity. In conclusion, our study presents a novel function of Cks1 in maintaining HSC/HPC homeostasis and shows that Cks1 is a possible target in therapies aimed at the SCF(Skp2)/Cks1 complex that controls CKI abundance and cancer cell proliferation.
authors.affiliation: III. Medical Department, Technische Universität München, Munich, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Tomiatti
authors.affiliation: III. Medical Department, Technische Universität München, Munich, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Istvánffy
authors.affiliation: III. Medical Department, Technische Universität München, Munich, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Pietschmann
authors.affiliation: III. Medical Department, Technische Universität München, Munich, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Kratzat
authors.affiliation: III. Medical Department, Technische Universität München, Munich, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Hoellein
authors.affiliation: Institute of Pathology, Eberhard-Karls-Universität Tübingen, Tübingen, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Quintanilla-Fend
authors.affiliation: 1] III. Medical Department, Technische Universität München, Munich, Germany [2] I. Medical Department, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.
authors.forename: N
authors.initials: N
authors.lastname: von Bubnoff
authors.affiliation: 1] III. Medical Department, Technische Universität München, Munich, Germany [2] German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Peschel
authors.affiliation: III. Medical Department, Technische Universität München, Munich, Germany.
authors.forename: R A J
authors.initials: RA
authors.lastname: Oostendorp
authors.affiliation: 1] III. Medical Department, Technische Universität München, Munich, Germany [2] German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Keller
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D042846:CDC2-CDC28 Kinases / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology*; D016207:Cytokines / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D012038:Regeneration / Q000187:drug effects; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism
chemical_list: D016207:Cytokines; D047428:Protein Kinase Inhibitors; D044786:S-Phase Kinase-Associated Proteins; D042846:CDC2-CDC28 Kinases; C474110:Cks1 protein, mouse