title: Gfer is a critical regulator of HSC proliferation.
abstract: Hematopoietic stem cells (HSC) are a relatively quiescent pool of cells that perform the arduous task of replacing the short-lived mature cells of the peripheral blood. While a rapid expansion of HSCs under periods of hematological stress is warranted, their enhanced proliferation during homeostasis leads to loss of function. We recently reported that in HSCs, the evolutionarily conserved growth factor erv1-like (Gfer) acts to counter jun activation domain-binding protein 1 (Jab1)-mediated nuclear export and destabilization of the cell cycle inhibitor, p27kip1, by directly binding to and sequestering the COP9 signalosome (CSN) subunit. Through this mechanism, Gfer promotes quiescence and maintains the functional integrity of HSCs. Here, we extend our study to demonstrate an association between Gfer and Ca2+/calmodulin-dependent protein kinase IV (CaMKIV) in the regulation of HSC proliferation. Highly proliferative and functionally deficient Camk4-/- HSCs possess significantly lower levels of Gfer and p27kip1. Ectopic expression of Gfer restores quiescence and elevates p27kip1 expression in Camk4-/- HSCs. These results further substantiate a critical role for Gfer in the restriction of unwarranted proliferation in HSCs through the inhibition of Jab1 and subsequent stabilization and nuclear retention of p27kip1. This Gfer-mediated pro-quiescence mechanism could be therapeutically exploited in the treatment of hematological malignancies associated with elevated Jab1 and reduced p27kip1.
authors.affiliation: James Graham Brown Cancer Center and Owensboro Cancer Research Program, Department of Pharmacology and Toxicology, University of Louisville, Lousville, KY, USA. uma.sankar@louisville.edu
authors.forename: Uma
authors.initials: U
authors.lastname: Sankar
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Means
mesh_terms: D000818:Animals; D000075686:COP9 Signalosome Complex; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D003579:Cytochrome Reductases / Q000737:chemistry / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D050862:Oxidoreductases Acting on Sulfur Group Donors; D010447:Peptide Hydrolases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003579:Cytochrome Reductases; C500897:GFER protein, human; D050862:Oxidoreductases Acting on Sulfur Group Donors; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; C517685:Camk4 protein, mouse; D010447:Peptide Hydrolases; C501490:Cops5 protein, mouse; D000075686:COP9 Signalosome Complex