SOX9 is targeted for proteasomal degradation by the E3 ligase FBW7 in response to DNA damage.
SOX9 is targeted for proteasomal degradation by the E3 ligase FBW7 in response to DNA damage.
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DOI：
10.1093/nar/gkw748
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发表时间：
2016-10-14
影响因子：
14.9
通讯作者：
Pine SR
中科院分区：
文献类型：
--
作者：
Hong X;Liu W;Song R;Shah JJ;Feng X;Tsang CK;Morgan KM;Bunting SF;Inuzuka H;Zheng XF;Shen Z;Sabaawy HE;Liu L;Pine SR
SOX9编码一种转录因子，在整个发育和组织稳态过程中控制细胞命运规范。升高的SOX9通过增加细胞增殖和上皮-间质转化参与人类肿瘤的发生和发展。我们发现，在紫外线照射或基因毒性化疗药物的作用下，SOX9在各种癌症类型和正常上皮细胞中通过独立于p53、ATM、ATR和DNA-PK的途径被积极降解。SOX9被GSK3β磷酸化，促进SOX9与F-box蛋白FBW7α结合，FBW7α是一种在DNA损伤反应途径中起作用的E3连接酶。FBW7α结合到T236-T240的SOX9 K2结构域，靶向SOX9随后的泛素化和蛋白酶体破坏。基因毒性应激后外源性过表达SOX9可提高细胞存活率。我们的研究结果揭示了SOX9稳定性的一种新的调控机制，并揭示了SOX9在细胞对DNA损伤反应中的独特功能。癌症中FBW7-SOX9轴的这种新机制可能与治疗耐药有关。
SOX9 encodes a transcription factor that governs cell fate specification throughout development and tissue homeostasis. Elevated SOX9 is implicated in the genesis and progression of human tumors by increasing cell proliferation and epithelial-mesenchymal transition. We found that in response to UV irradiation or genotoxic chemotherapeutics, SOX9 is actively degraded in various cancer types and in normal epithelial cells, through a pathway independent of p53, ATM, ATR and DNA-PK. SOX9 is phosphorylated by GSK3β, facilitating the binding of SOX9 to the F-box protein FBW7α, an E3 ligase that functions in the DNA damage response pathway. The binding of FBW7α to the SOX9 K2 domain at T236-T240 targets SOX9 for subsequent ubiquitination and proteasomal destruction. Exogenous overexpression of SOX9 after genotoxic stress increases cell survival. Our findings reveal a novel regulatory mechanism for SOX9 stability and uncover a unique function of SOX9 in the cellular response to DNA damage. This new mechanism underlying a FBW7-SOX9 axis in cancer could have implications in therapy resistance.
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影响因子：
64.8
作者：
Inuzuka, Hiroyuki;Shaik, Shavali;Onoyama, Ichiro;Gao, Daming;Tseng, Alan;Maser, Richard S.;Zhai, Bo;Wan, Lixin;Gutierrez, Alejandro;Lau, Alan W.;Xiao, Yonghong;Christie, Amanda L.;Aster, Jon;Settleman, Jeffrey;Gygi, Steven P.;Kung, Andrew L.;Look, Thomas;Nakayama, Keiichi I.;DePinho, Ronald A.;Wei, Wenyi
通讯作者：
Wei, Wenyi
DOI：
10.1083/jcb.200311021
发表时间：
2004-07-05
期刊：
The Journal of cell biology
影响因子：
--
作者：
Blache P;van de Wetering M;Duluc I;Domon C;Berta P;Freund JN;Clevers H;Jay P
通讯作者：
Jay P
影响因子：
10.5
作者：
Akiyama, H;Chaboissier, MC;de Crombrugghe, B
通讯作者：
de Crombrugghe, B
影响因子：
8
作者：
Lakin, ND;Hann, BC;Jackson, SP
通讯作者：
Jackson, SP
影响因子：
8.8
作者：
Fukushima H;Matsumoto A;Inuzuka H;Zhai B;Lau AW;Wan L;Gao D;Shaik S;Yuan M;Gygi SP;Jimi E;Asara JM;Nakayama K;Nakayama KI;Wei W
通讯作者：
Wei W