Cooperative effect of ribosomal protein s19 and Pim-1 kinase on murine c-Myc expression and myeloid/erythroid cellularity.
Diamond-Blackfan anemia is a bone marrow failure syndrome associated with heterozygous mutations in the ribosomal protein S19 (RPS19) gene in a subgroup of patients. One of the interacting partners with RPS19 is the oncoprotein PIM-1 kinase. We intercrossed Rps19 ( +/- ) and Pim-1 ( -/- ) mice strains to study the effect from the disruption of both genes. The double mutant (Rps19 ( +/- ) Pim-1 ( -/- )) mice display normal growth with increased peripheral white and red blood cell counts when compared to the w.t. mice (Rps19 ( +/+ ) Pim-1 ( +/+ )). Molecular analysis of bone marrow cells in Rps19 ( +/- ) Pim-1 ( -/- ) mice revealed up-regulated levels of c-Myc and the anti-apoptotic factors Bcl(2), Bcl(XL), and Mcl-1. This is associated with a reduction of the apoptotic factors Bak and Caspase 3 as well as the cell cycle regulator p21. Our findings suggest that combined Rps19 insufficiency and Pim-1 deficiency promote murine myeloid cell growth through a deregulation of c-Myc and a simultaneous up-regulation of anti-apoptotic Bcl proteins.
Fröjmark
Anne-Sophie
AS
Department of Genetics and Pathology, the Rudbeck Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
Badhai
Jitendra
J
Klar
Joakim
J
Thuveson
Maria
M
Schuster
Jens
J
Dahl
Niklas
N
D029503:Anemia, Diamond-Blackfan / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D001853:Bone Marrow / Q000473:pathology; D049109:Cell Proliferation; D004920:Erythropoiesis; D005786:Gene Expression Regulation; D051379:Mice; D009154:Mutation; D022423:Myeloid Cells / Q000166:cytology; D038042:Myelopoiesis; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D051573:Proto-Oncogene Proteins c-pim-1 / Q000235:genetics* / Q000378:metabolism; D012269:Ribosomal Proteins / Q000235:genetics* / Q000378:metabolism; D013154:Spleen / Q000473:pathology
D016271:Proto-Oncogene Proteins c-myc; D012269:Ribosomal Proteins; C040343:ribosomal protein S19; D051573:Proto-Oncogene Proteins c-pim-1