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Hematopoietic stem cell quiescence and function are controlled by the CYLD-TRAF2-p38MAPK pathway.

Tesio M, Tang Y, Müdder K, Saini M, von Paleske L, Macintyre E, Pasparakis M, Waisman A, Trumpp A - J. Exp. Med. (2015)

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.

View Article: PubMed Central - HTML - PubMed

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.

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CYLD–TRAF2 interaction has no significant effect on NF-κB signaling. (A) IκBα levels in BM HSCs from control and CYLDex7/8−/− mice. (B) Expression analysis using qRT-PCR of NF-κB target genes in BM HSCs sorted from control and CYLDex7/8−/− mice. (C) NIK expression analyzed by flow cytometry in BM HSCs from control and CYLDex7/8−/− mice. Results are shown of two (A: 4/4; B: 5/7) or three (C: 4/6) independent experiments, with the numbers of analyzed control/mutant mice indicated in parentheses. Error bars indicate SEM. *, P < 0.05.
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fig5: CYLD–TRAF2 interaction has no significant effect on NF-κB signaling. (A) IκBα levels in BM HSCs from control and CYLDex7/8−/− mice. (B) Expression analysis using qRT-PCR of NF-κB target genes in BM HSCs sorted from control and CYLDex7/8−/− mice. (C) NIK expression analyzed by flow cytometry in BM HSCs from control and CYLDex7/8−/− mice. Results are shown of two (A: 4/4; B: 5/7) or three (C: 4/6) independent experiments, with the numbers of analyzed control/mutant mice indicated in parentheses. Error bars indicate SEM. *, P < 0.05.

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).


Hematopoietic stem cell quiescence and function are controlled by the CYLD-TRAF2-p38MAPK pathway.

Tesio M, Tang Y, Müdder K, Saini M, von Paleske L, Macintyre E, Pasparakis M, Waisman A, Trumpp A - J. Exp. Med. (2015)

CYLD–TRAF2 interaction has no significant effect on NF-κB signaling. (A) IκBα levels in BM HSCs from control and CYLDex7/8−/− mice. (B) Expression analysis using qRT-PCR of NF-κB target genes in BM HSCs sorted from control and CYLDex7/8−/− mice. (C) NIK expression analyzed by flow cytometry in BM HSCs from control and CYLDex7/8−/− mice. Results are shown of two (A: 4/4; B: 5/7) or three (C: 4/6) independent experiments, with the numbers of analyzed control/mutant mice indicated in parentheses. Error bars indicate SEM. *, P < 0.05.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4387289&req=5

fig5: CYLD–TRAF2 interaction has no significant effect on NF-κB signaling. (A) IκBα levels in BM HSCs from control and CYLDex7/8−/− mice. (B) Expression analysis using qRT-PCR of NF-κB target genes in BM HSCs sorted from control and CYLDex7/8−/− mice. (C) NIK expression analyzed by flow cytometry in BM HSCs from control and CYLDex7/8−/− mice. Results are shown of two (A: 4/4; B: 5/7) or three (C: 4/6) independent experiments, with the numbers of analyzed control/mutant mice indicated in parentheses. Error bars indicate SEM. *, P < 0.05.
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).

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.

View Article: PubMed Central - HTML - PubMed

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
Related in: MedlinePlus