title: PKR regulates proliferation, differentiation, and survival of murine hematopoietic stem/progenitor cells.
abstract: Protein kinase R (PKR) is an interferon (IFN)-inducible, double-stranded RNA-activated kinase that initiates apoptosis in response to cellular stress. To determine the role of PKR in hematopoiesis, we developed transgenic mouse models that express either human PKR (TgPKR) or a dominant-negative PKR (TgDNPKR) mutant specifically in hematopoietic tissues. Significantly, peripheral blood counts from TgPKR mice decrease with age in association with dysplastic marrow changes. TgPKR mice have reduced colony-forming capacity and the colonies also are more sensitive to hematopoietic stresses. Furthermore, TgPKR mice have fewer hematopoietic stem/progenitor cells (HSPCs), and the percentage of quiescent (G0) HSPCs is increased. Importantly, treatment of TgPKR bone marrow (BM) with a PKR inhibitor specifically rescues sensitivity to growth factor deprivation. In contrast, marrow from PKR knockout (PKRKO) mice has increased potential for colony formation and HSPCs are more actively proliferating and resistant to stress. Significantly, TgPKR HSPCs have increased expression of p21 and IFN regulatory factor, whereas cells from PKRKO mice display mechanisms indicative of proliferation such as reduced eukaryotic initiation factor 2α phosphorylation, increased extracellular signal-regulated protein kinases 1 and 2 phosphorylation, and increased CDK2 expression. Collectively, data reveal that PKR is an unrecognized but important regulator of HSPC cell fate and may play a role in the pathogenesis of BM failure.
authors: Department of Medicine, Division of Hematology and Oncology and the University of Florida Shands Cancer Center, Gainesville, FL 32610, USA.
authors: Xiangfei
authors: X
authors: Liu
authors: Richard L
authors: RL
authors: Bennett
authors: Xiaodong
authors: X
authors: Cheng
authors: Michael
authors: M
authors: Byrne
authors: Mary K
authors: MK
authors: Reinhard
authors: W Stratford
authors: WS
authors: May
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001855:Bone Marrow Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D005799:Genes, Dominant; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000235:genetics; D011836:Radiation Tolerance; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019892:eIF-2 Kinase
chemical_list: D016207:Cytokines; D012333:RNA, Messenger; D019892:eIF-2 Kinase
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