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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: This phenotype is dependent on the interactions between CYLD and its substrate TRAF2 (tumor necrosis factor-associated factor 2).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.Pharmacological inhibition of p38MAPK rescued the phenotype of CYLD loss, identifying the CYLD-TRAF2-p38MAPK pathway as a novel important regulator of HSC function restricting HSC cycling and promoting dormancy.

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: This phenotype is dependent on the interactions between CYLD and its substrate TRAF2 (tumor necrosis factor-associated factor 2).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.Pharmacological inhibition of p38MAPK rescued the phenotype of CYLD loss, identifying the CYLD-TRAF2-p38MAPK pathway as a novel important regulator of HSC function restricting HSC cycling and promoting dormancy.

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