Calmodulin-dependent protein kinase IV regulates hematopoietic stem cell maintenance.
The hematopoietic stem cell (HSC) gives rise to all mature, terminally differentiated cells of the blood. Here we show that calmodulin-dependent protein kinase IV (CaMKIV) is present in c-Kit+ ScaI+ Lin(-/low) hematopoietic progenitor cells (KLS cells) and that its absence results in hematopoietic failure, characterized by a diminished KLS cell population and by an inability of these cells to reconstitute blood cells upon serial transplantation. KLS cell failure in the absence of CaMKIV is correlated with increased apoptosis and proliferation of these cells in vivo and in vitro. In turn, these cell biological defects are correlated with decreases in CREB-serine 133 phosphorylation as well as in CREB-binding protein (CBP) and Bcl-2 levels. Re-expression of CaMKIV in Camk4-/- KLS cells results in the rescue of the proliferation defects in vitro as well as in the restoration of CBP and Bcl-2 to wild type levels. These studies show that CaMKIV is a regulator of HSC homeostasis and suggest that its effects may be in part mediated via regulation of CBP and Bcl-2.
Kitsos
Christine M
CM
Department of Pharmacology and Cancer Biology, Duke University, Medical Center, Durham, North Carolina 27715, USA.
Sankar
Uma
U
Illario
Maddalena
M
Colomer-Font
Josep M
JM
Duncan
Andrew W
AW
Ribar
Thomas J
TJ
Reya
Tannishtha
T
Means
Anthony R
AR
D000818:Animals; D017209:Apoptosis; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D017690:Cell Transplantation; D002478:Cells, Cultured; D015971:Gene Expression Regulation, Enzymologic; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000201:enzymology* / Q000502:physiology; D006706:Homeostasis; D051379:Mice; D020297:Mice, Congenic; D018345:Mice, Knockout; D008954:Models, Biological; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D013997:Time Factors; D014184:Transplantation, Homologous
D019253:Proto-Oncogene Proteins c-bcl-2; D012694:Serine; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C517685:Camk4 protein, mouse