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Publication : Constitutive Activation of NF-κB Pathway in Hematopoietic Stem Cells Causes Loss of Quiescence and Deregulated Transcription Factor Networks.

First Author  Nakagawa MM Year  2018
Journal  Front Cell Dev Biol Volume  6
Pages  143 PubMed ID  30425986
Mgi Jnum  J:290021 Mgi Id  MGI:6437622
Doi  10.3389/fcell.2018.00143 Citation  Nakagawa MM, et al. (2018) Constitutive Activation of NF-kappaB Pathway in Hematopoietic Stem Cells Causes Loss of Quiescence and Deregulated Transcription Factor Networks. Front Cell Dev Biol 6:143
abstractText  Identifying physiological roles of specific signaling pathways that regulate hematopoietic stem cell (HSC) functions may lead to new treatment strategies and therapeutic interventions for hematologic disorders. Here, we provide genetic evidence that constitutive activation of NF-kappaB in HSCs results in reduced pool size, repopulation capacities, and quiescence of HSCs. Global transcriptional profiling and bioinformatics studies identified loss of 'stemness' and 'quiescence' signatures in HSCs with deregulated NF-kappaB activation. In particular, gene set enrichment analysis identified upregulation of cyclin dependent kinase- Ccnd1 and down regulation of cyclin dependent kinase inhibitor p57(kip2) . Interestingly, constitutive activation of NF-kappaB is sufficient to alter the regulatory circuits of transcription factors (TFs) that are critical to HSC self-renewal and functions. Molecular studies identified Junb, as one of the direct targets of NF-kappaB in hematopoietic cells. In essence, these studies demonstrate that aberrant activation of NF-kappaB signals impairs HSC quiescence and functions and alters the 'TF networks' in HSCs.
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