TRAF6 maintains mammary stem cells and promotes pregnancy-induced mammary epithelial cell expansion
TRAF6 maintains mammary stem cells and promotes pregnancy-induced mammary epithelial cell expansion
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TRAF6 维持乳腺干细胞并促进妊娠诱导的乳腺上皮细胞扩张
DOI：
10.1038/s42003-019-0547-7
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发表时间：
2019
影响因子：
5.9
通讯作者：
Inoue Jun-ichiro
中科院分区：
文献类型：
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作者：
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
核因子（NF）-κB受体激活因子（RANK）信号通路促进妊娠依赖性上皮细胞分化和扩增，从而促进乳腺发育，这需要NF-κB通路依赖性Cyclin D1诱导和DNA结合抑制因子2（Id 2）通路依赖性抗凋亡基因诱导。然而，肿瘤坏死因子受体相关因子6（TRAF 6）的作用仍然不清楚，尽管它在RANK信号转导的要求。在此我们表明TRAF 6对于乳腺干细胞的维持和妊娠诱导的上皮细胞扩增都是至关重要的。TRAF 6缺陷损害磷酸肌醇3-激酶（PI 3 K）/AKT和经典NF-κB通路，而非经典NF-κB信号传导保持功能。因此，我们认为TRAF 6通过激活PI 3 K/AKT信号通路诱导视网膜母细胞瘤磷酸化，并与非经典NF-κB通路依赖的Cyclin D1诱导相一致，从而促进细胞增殖。此外，TRAF 6通过激活经典NF-κB信号传导以诱导具有Id 2途径的抗凋亡基因来抑制凋亡。因此，TRAF 6依赖性和非依赖性RANK信号的适当协调可能建立乳腺形成。
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.