Cytoplasmic TRAF4 contributes to the activation of p70s6k signaling pathway in breast cancer
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Hua-Yan Ren1, Jian Wang1, Fan Yang1, Xiao-Li Zhang1, Ai-Lian Wang1, Li-Li Sun1, Ke-Xin Diao1, En-Hua Wang1, Xiao-Yi Mi1
1Department of Pathology, First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang 110001, P.R. China
Xiao-Yi Mi, e-mail: [email protected]
Keywords: TRAF4, p70s6k, TRAF2, cell proliferation, breast cancer
Received: August 20, 2014 Accepted: December 18, 2014 Published: January 09, 2015
Tumor necrosis factor receptor associated factor 4 (TRAF4) is an important adaptor protein that plays a significant role in several signaling pathways. By studying the relationship between TRAF4 and 70 kDa ribosomal protein S6 kinase (p70s6k) in vivo, we demonstrated that cytoplasmic TRAF4 was correlated with the activation of p70s6k in breast cancer. Moreover, we found that cytoplasmic TRAF4 expression in breast cancer patients was significantly associated with a poor prognosis. To determine the exact mechanism, we analyzed the interaction between TRAF4 and p70s6k and identified the Zinc fingers domain of TRAF4 was responsible for their interaction in MCF7 cells. Furthermore, we found that activation of p70s6k/S6 signaling pathway by TRAF4 requires the mammalian target of rapamycin (mTOR) activity; TRAF4 acted as a sensitizer. Tumor necrosis factor receptor associated factor 2 (TRAF2), as a binding partner of TRAF4, could also promoted activation of p70s6k signaling via upregulating cytoplasm expression of TRAF4 and played a critical role in TNFa-induced activation of p70s6k/S6 pathway. Finally, we demonstrated p70s6k/S6 signaling pathway played an important role in the promoting function of TRAF4 on cell proliferation. In summary, our work suggests a new direction for understanding the oncogenic function of TRAF4 in breast cancer.
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