TRAF6 maintains mammary stem cells and promotes pregnancy-induced mammary epithelial cell expansion

Mizuki Yamamoto, Chiho Abe, Sakura Wakinaga, Kota Sakane, Yo Yumiketa, Yuu Taguchi, Takayuki Matsumura, Kosuke Ishikawa, Jiro Fujimoto, Kentaro Semba, Maki Miyauchi, Taishin Akiyama, Jun ichiro Inoue

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Article number292
JournalCommunications Biology
Volume2
Issue number1
DOIs
Publication statusPublished - 2019 Dec 1

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Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
tumor necrosis factors
Stem cells
breasts
stem cells
Breast
epithelial cells
Stem Cells
Epithelial Cells
pregnancy
Pregnancy
receptors
1-Phosphatidylinositol 4-Kinase
Cyclin D1
Human Mammary Glands
Phosphatidylinositols
phosphatidylinositol 3-kinase
cyclins
mammary glands
Phosphotransferases

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Medicine (miscellaneous)

Cite this

Yamamoto, M., Abe, C., Wakinaga, S., Sakane, K., Yumiketa, Y., Taguchi, Y., ... Inoue, J. I. (2019). TRAF6 maintains mammary stem cells and promotes pregnancy-induced mammary epithelial cell expansion. Communications Biology, 2(1), [292]. https://doi.org/10.1038/s42003-019-0547-7

TRAF6 maintains mammary stem cells and promotes pregnancy-induced mammary epithelial cell expansion. / Yamamoto, Mizuki; Abe, Chiho; Wakinaga, Sakura; Sakane, Kota; Yumiketa, Yo; Taguchi, Yuu; Matsumura, Takayuki; Ishikawa, Kosuke; Fujimoto, Jiro; Semba, Kentaro; Miyauchi, Maki; Akiyama, Taishin; Inoue, Jun ichiro.

In: Communications Biology, Vol. 2, No. 1, 292, 01.12.2019.

Research output: Contribution to journalArticle

Yamamoto, M, Abe, C, Wakinaga, S, Sakane, K, Yumiketa, Y, Taguchi, Y, Matsumura, T, Ishikawa, K, Fujimoto, J, Semba, K, Miyauchi, M, Akiyama, T & Inoue, JI 2019, 'TRAF6 maintains mammary stem cells and promotes pregnancy-induced mammary epithelial cell expansion', Communications Biology, vol. 2, no. 1, 292. https://doi.org/10.1038/s42003-019-0547-7
Yamamoto, Mizuki ; Abe, Chiho ; Wakinaga, Sakura ; Sakane, Kota ; Yumiketa, Yo ; Taguchi, Yuu ; Matsumura, Takayuki ; Ishikawa, Kosuke ; Fujimoto, Jiro ; Semba, Kentaro ; Miyauchi, Maki ; Akiyama, Taishin ; Inoue, Jun ichiro. / TRAF6 maintains mammary stem cells and promotes pregnancy-induced mammary epithelial cell expansion. In: Communications Biology. 2019 ; Vol. 2, No. 1.
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