title: Simultaneous deletion of p21Cip1/Waf1 and caspase-3 accelerates proliferation and partially rescues the differentiation defects of caspase-3 deficient hematopoietic stem cells.
abstract: Specialized blood cells are generated through the entire life of an organism by differentiation of a small number of hematopoietic stem cells (HSC). There are strictly regulated mechanisms assuring a constant and controlled production of mature blood cells. Although such mechanisms are not completely understood, some factors regulating cell cycle and differentiation have been identified. We have previously shown that Caspase-3 is an important regulator of HSC homeostasis and cytokine responsiveness. p21cip1/waf1 is a known cell cycle regulator, however its role in stem cell homeostasis seems to be limited. Several reports indicate interactions between p21cip1/waf1 and Caspase-3 in a cell type dependent manner. Here we studied the impact of simultaneous depletion of both factors on HSC homeostasis. Depletion of both Caspase-3 and p21cip1/waf1 resulted in an even more pronounced increase in the frequency of hematopoietic stem and progenitor cells. In addition, simultaneous deletion of both genes revealed a further increase of cell proliferation compared to single knock-outs and WT control mice, while apoptosis or self-renewal ability were not affected in any of the genotypes. Upon transplantation, p21cip1/waf1-/- bone marrow did not reveal significant alterations in engraftment of lethally irradiated mice, while Caspase-3 deficient HSPC displayed a significant reduction of blood cell production. However, when both p21cip1/waf1 and Caspase-3 were eliminated this differentiation defect caused by Caspase-3 deficiency was abrogated.
authors.affiliation: Department of Internal Medicine III, Division of Hematology/Oncology, University of Bonn, Bonn, Germany.
authors.forename: Carmen
authors.initials: C
authors.lastname: Carrillo García
authors.affiliation: Department of Internal Medicine III, Division of Hematology/Oncology, University of Bonn, Bonn, Germany.
authors.forename: Tamara
authors.initials: T
authors.lastname: Riedt
authors.affiliation: Department of Internal Medicine III, Division of Hematology/Oncology, University of Bonn, Bonn, Germany.
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Internal Medicine III, Division of Hematology/Oncology, University of Bonn, Bonn, Germany.
authors.forename: Manuela
authors.initials: M
authors.lastname: Dotten
authors.affiliation: Department of Internal Medicine III, Division of Hematology/Oncology, University of Bonn, Bonn, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Brossart
authors.affiliation: Department of Internal Medicine III, Division of Hematology/Oncology, University of Bonn, Bonn, Germany.
authors.forename: Viktor
authors.initials: V
authors.lastname: Janzen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D053148:Caspase 3 / Q000172:deficiency* / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics; D000066673:Cell Self Renewal / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000172:deficiency* / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D055786:Gene Knockout Techniques; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D051379:Mice; D015398:Signal Transduction / Q000235:genetics
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D053148:Caspase 3