التفاصيل البيبلوغرافية
| العنوان: |
Epsins 1 and 2 promote NEMO linear ubiquitination via LUBAC to drive breast cancer development. |
| المؤلفون: |
Kai Song1, Xiaofeng Cai1,2, Yunzhou Dong1, Hao Wu1, Yong Wei3,4, Shankavaram, Uma T.5, Kui Cui1, Yang Lee1, Bo Zhu1, Bhattacharjee, Sudarshan1, Beibei Wang1, Kun Zhang1, Aiyun Wen1, Scott Wong1, Lili Yu1, Lijun Xia2, Welm, Alana L.6, Bielenberg, Diane R.1, Camphausen, Kevin A.5, Yibin Kang3,4 |
| المصدر: |
Journal of Clinical Investigation. Jan2021, Vol. 131 Issue 1, p1-13. 13p. |
| مصطلحات موضوعية: |
*BREAST cancer, *UBIQUITINATION, *CELL death, *ADAPTOR proteins, *UBIQUITIN |
| مستخلص: |
Estrogen receptor-negative (ER-negative) breast cancer is thought to be more malignant and devastating than ER-positive breast cancer. ER-negative breast cancer exhibits elevated NF-κB activity, but how this abnormally high NF-κB activity is maintained is poorly understood. The importance of linear ubiquitination, which is generated by the linear ubiquitin chain assembly complex (LUBAC), is increasingly appreciated in NF-κB signaling, which regulates cell activation and death. Here, we showed that epsin proteins, a family of ubiquitin-binding endocytic adaptors, interacted with LUBAC via its ubiquitin-interacting motif and bound LUBAC's bona fide substrate NEMO via its N-terminal homolog (ENTH) domain. Furthermore, epsins promoted NF-κB essential modulator (NEMO) linear ubiquitination and served as scaffolds for recruiting other components of the IκB kinase (IKK) complex, resulting in the heightened IKK activation and sustained NF-κB signaling essential for the development of ER-negative breast cancer. Heightened epsin levels in ER-negative human breast cancer are associated with poor relapse-free survival. We showed that transgenic and pharmacological approaches eliminating epsins potently impeded breast cancer development in both spontaneous and patient-derived xenograft breast cancer mouse models. Our findings established the pivotal role epsins played in promoting breast cancer. Thus, targeting epsins may represent a strategy to restrain NF-κB signaling and provide an important perspective into ER-negative breast cancer treatment. [ABSTRACT FROM AUTHOR] |
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