TRAF6 maintains mammary stem cells and promotes pregnancy-induced mammary epithelial cell expansion.
Adipose Tissue
/ metabolism
Animals
Apoptosis
Cell Line
Cell Proliferation
Cyclin D1
/ metabolism
Epithelial Cells
/ metabolism
Female
Mammary Glands, Animal
/ growth & development
Mice, Inbred BALB C
Mice, Knockout
NF-kappa B
/ metabolism
Phosphatidylinositol 3-Kinase
/ metabolism
Phosphorylation
Pregnancy
Proto-Oncogene Proteins c-akt
/ metabolism
Receptor Activator of Nuclear Factor-kappa B
/ metabolism
Retinoblastoma Protein
/ metabolism
Signal Transduction
Stem Cells
/ metabolism
TNF Receptor-Associated Factor 6
/ deficiency
Cell growth
Cell proliferation
Organogenesis
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
2019
2019
Historique:
received:
27
09
2018
accepted:
15
07
2019
entrez:
10
8
2019
pubmed:
10
8
2019
medline:
10
8
2019
Statut:
epublish
Résumé
Receptor activator of nuclear factor (NF)-κB (RANK) signaling promotes pregnancy-dependent epithelial cell differentiation and expansion for mammary gland development, which requires NF-κB pathway-dependent Cyclin D1 induction and inhibitor of DNA binding 2 (Id2) pathway-dependent anti-apoptotic gene induction. However, the roles of tumor necrosis factor receptor-associated factor 6 (TRAF6) remain unclear despite its requirement in RANK signaling. Here we show that TRAF6 is crucial for both mammary stem cell maintenance and pregnancy-induced epithelial cell expansion. TRAF6 deficiency impairs phosphoinositide 3-kinase (PI3K)/AKT and canonical NF-κB pathways, whereas noncanonical NF-κB signaling remains functional. Therefore, we propose that TRAF6 promotes cell proliferation by activating PI3K/AKT signaling to induce retinoblastoma phosphorylation in concert with noncanonical NF-κB pathway-dependent Cyclin D1 induction. Furthermore, TRAF6 inhibits apoptosis by activating canonical NF-κB signaling to induce anti-apoptotic genes with the Id2 pathway. Therefore, proper orchestration of TRAF6-dependent and -independent RANK signals likely establishes mammary gland formation.
Identifiants
pubmed: 31396572
doi: 10.1038/s42003-019-0547-7
pii: 547
pmc: PMC6684589
doi:
Substances chimiques
Ccnd1 protein, mouse
0
NF-kappa B
0
Receptor Activator of Nuclear Factor-kappa B
0
Retinoblastoma Protein
0
TNF Receptor-Associated Factor 6
0
TRAF6 protein, mouse
0
Tnfrsf11a protein, mouse
0
Cyclin D1
136601-57-5
Phosphatidylinositol 3-Kinase
EC 2.7.1.137
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Pagination
292Déclaration de conflit d'intérêts
Competing interestsThe authors declare no competing interests.
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