Fbxw7α- and GSK3-mediated degradation of p100 is a pro-survival mechanism in multiple myeloma.
Fbxw7α- and GSK3-mediated degradation of p100 is a pro-survival mechanism in multiple myeloma.
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DOI：
10.1038/ncb2463
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发表时间：
2012-03-04
影响因子：
21.3
通讯作者：
中科院分区：
文献类型：
--
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Fbxw 7 α是F-box蛋白家族的成员，是SCF（Skp 1/Cul 1/F-box蛋白）泛素连接酶复合物的底物靶向亚基。利用差异纯化和质谱分析，我们鉴定了NF-κB信号传导抑制剂p100作为Fbxw 7 α的相互作用物。p100在细胞核中被Fbxw 7 α组成性靶向蛋白酶体降解，Fbxw 7 α识别被GSK 3磷酸化的保守基序。非经典NF-κB信号传导的有效激活依赖于通过Fbxw 7 α降解或通过p100羧基端新鉴定的核输出信号排除而消除核p100。在具有组成性非典型NF-κB活性的多发性骨髓瘤细胞中，稳定的p100突变体的表达、组成性核p100突变体的表达、Fbxw 7 α沉默或GSK 3的抑制导致细胞系统和异种移植模型中的细胞凋亡。因此，在多发性骨髓瘤中，Fbxw 7 α和GSK 3通过控制p100降解作为促存活因子发挥作用。
Fbxw7α is a member of the F-box family of proteins, which function as the substrate-targeting subunits of SCF (Skp1/Cul1/F-box protein) ubiquitin ligase complexes. Using differential purifications and mass spectrometry, we identified p100, an inhibitor of NF-κB signalling, as an interactor of Fbxw7α. p100 is constitutively targeted in the nucleus for proteasomal degradation by Fbxw7α, which recognizes a conserved motif phosphorylated by GSK3. Efficient activation of non-canonical NF-κB signalling is dependent on the elimination of nuclear p100 through either degradation by Fbxw7α or exclusion by a newly identified nuclear export signal in the carboxy terminus of p100. Expression of a stable p100 mutant, expression of a constitutively nuclear p100 mutant, Fbxw7α silencing or inhibition of GSK3 in multiple myeloma cells with constitutive non-canonical NF-κB activity results in apoptosis both in cell systems and xenotransplant models. Thus, in multiple myeloma, Fbxw7α and GSK3 function as pro-survival factors through the control of p100 degradation.
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