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«3. Medizinische Klinik und Poliklinik – Hämatologische Forschung Cks1 is a critical regulator of hematopoietic stem cell cycling, quiescence and ...»

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Figure 6: High Cks1 transcript levels in the CD34- LSK subset of WT mice................ 54  Figure 7: Normal steady state adult hematopoiesis in Cks1-deficient mice.................. 56  Figure 8: BM analysis in WT and Cks1-/-mice. Representative FACS Analysis........... 57  Figure 9: Decreased absolute HPC numbers and increased relative HSC numbers in Cks1-/- mice.

Figure 10: Loss of Cks1 results in decreased colony formation.

Figure 11: Decreased colony formation and progenitor cell number after cultivation of Lin- Cks1-/- cells on stromal cells.

Figure 12: Cks1-/- cells proliferate slower in culture.

Figure 13: Cks1 regulates survival of progenitor cells in vitro.

Figure 14: Increased B cells- and decreased granulocytes frequency after cytotoxic stress in Cks1-/- mice.

Figure 15: Cks1 controls stress hematopoiesis in LSK cells: impaired LSK regeneration after cytotoxic stress.

Figure 16: Primary BM Transplantations. Cks1-/- BM cells are able to reconstitute recipient mice.

Figure 17: Secondary BM Transplantations. Increased engraftment of Cks1-/- cells... 72  Figure 18: Loss of Cks1 in LSK results in increased replating capability and increased LSK frequency after cultivating in vitro.

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Figure 19: Transplantations of CD150+ LSK cells. Decreased engraftment of Cks1deficient cells and increase in the Cks1-/- donor-delivered B cell population............... 76  Figure 20: Transplantations of CD150+ LSK cells. Loss of Cks1 leads to decreased engraftment and accumulation of CD150+ LSK.

Figure 21: Secondary transplantations of CD150+ LSK cells: Cks1 controls lineage differentiation.

Figure 22: Secondary transplantations of CD150+ LSK cells: Cks1-/- HSC proliferate slower.

Figure 23: Bone marrow analysis in WT, Cks1-/-, p27-/- and DKO mice

Figure 24: Concomitant loss of Cks1 and p27 in BM cells results in better survival in vitro compared to Cks1-/- or p27-/- cells.

Figure 25: Cks1 controls the regeneration of mature lineages after cytotoxic stress through p27 regulation.

Figure 26 (on page 87): Primary BM Transplantations. Analysis of the mature populations.

Figure 27: Primary BM Transplantations. Analysis of HSC/HPC.

Figure 28: Blood analysis of secondary BM Transplantations. p27 controls lymphoid lineage differentiation.

Figure 29: BM and spleen analysis of secondary BM Transplantations. p27 controls lymphoid lineage differentiation

Figure 30: Secondary Transplantations of whole bone marrow. Analysis of HSC/HPC91  Figure 31: Cks1 is up-regulated in CML.

Figure 32: Bcr-Abl expression in Cks1-/- BM cells results in decreased colony forming capability.

Figure 33: Hypothetical model representing the role of SCFSkp2-Cks1 in early hematopoiesis and the possible CKI involvement.

Figure 34: Hypothetical model representing possible regulators of Cks1 in early hematopoiesis.

ABBREVIATIONS

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DKO double knockout DMEM Dulbecco’s modified Eagle's medium DNA Desoxyribonucleic acid dNTP Deoxynucleotide DTT Dithiothreitole E2F E2 promoter binding factor EDTA Ethylenediaminetetraacetic acid FACS Fluorescence-activated cell sorting FANKL Fanconi anemia, complementation group L Fbxw7 F-box and WD40 domain protein 7 FCS Fetal Calf Serum FITC Fluorescein isothiocyanate FL Fetal liver Flk2 Fetal liver kinase 2 FLT3L Fms-like tyrosine kinase 3- ligand FoxM1 Forkhead box M1 FoxO3 Forkhead box 03 G Guanine G-CSF Granulocyte colony-stimulating factor GM-CSF Granulocyte Macrophage Colony Stimulating Factor GMP Granulocyte-monocyte-progenitor Gy Gray HBSS Hank's buffered salt solution HCl Hydrochloride HEK Human embryonic kidney HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid Hgb Hemoglobin HIF-1a Hypoxia-inducible factor-1alpha HRP Horse radish peroxidase HPS Hematopoietic progenitor cells HSC Hematopoietic stem cells Ig Immunoglobulin IkB Ikappa-B IL Interleukin

ABBREVIATIONS

–  –  –

SCF Stem cell factor SDS Sodium dodecyl sulfate SDS-PAGE Sodium dodecyl sulfate polyacrylamide gel electrophoresis sek Sekonds SEM Standard error of the mean Skp S-phase kinase-associated protein SLAM Signaling Lymphocytic Activation Molecule SOCS Suppressor of cytokine signalling ST-HSC Short-term repopulating hematopoietic stem cells TGF Transforming growth factor Suc1 suppressor of Cdc2 mutation T Thymine Tris Tris(hydroxymethyl)aminomethane TPO Thromopoietin Ub Ubiquitin VHL Von Hippel-Lindau protein Vs. Versus WBC White blood cells WT Wildtype

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