Hematopoietic stem cell quiescence and function are controlled by the CYLD-TRAF2-p38MAPK pathway.
Bottom Line: The status of long-term quiescence and dormancy guarantees the integrity of hematopoietic stem cells (HSCs) during adult homeostasis.However the molecular mechanisms regulating HSC dormancy remain poorly understood.Unexpectedly, the robust cycling of HSCs lacking functional CYLD-TRAF2 interactions was not elicited by increased NF-κB signaling, but instead by increased activation of the p38MAPK pathway.
Affiliation: Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany.Show MeSH
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Mentions: To further investigate the signaling cascade downstream of CYLD–TRAF2 interactions, we first determined whether mutant CYLDex7/8−/− HSCs exhibit increased canonical NF-κB signaling. To this purpose, we analyzed the degradation of IκBα, an inhibitory kinase which sequesters NF-κB dimers in the cytosol (Baeuerle and Baltimore, 1988). Surprisingly, not only were IκBα levels the same in mutant and WT HSCs (Fig. 5 A), they were not decreased after in vitro stimulation with TNF (not depicted). In line with these results, expression of the major NF-κB signaling effectors was not increased in CYLDex7/8−/− SKLCD150+CD48−CD34− cells, with the notable exception of NFKB2 (Fig. 5 B).
Affiliation: Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany.