Phosphorylation-dependent ubiquitination of cyclin D1 by the SCFFBX4-αB crystallin complex
Phosphorylation-dependent ubiquitination of cyclin D1 by the SCFFBX4-αB crystallin complex
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DOI：
10.1016/j.molcel.2006.09.007
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发表时间：
2006-11-03
期刊：
影响因子：
16
通讯作者：
Diehl, J. Alan
中科院分区：
文献类型：
--
作者：
Lin, Douglas I.;Barbash, Olena;Diehl, J. Alan
细胞周期蛋白D1原癌基因的生长因子依赖性积累通过其快速磷酸化依赖性蛋白水解来平衡。降解是由苏氨酸286磷酸化引发的，其通过未知的E3连接酶促进其泛素化。我们证明Thr 286磷酸化的细胞周期蛋白D1被Skp 1-Cul 1-F box（SCF）遍在蛋白连接酶识别，其中FBX 4和α B晶状体蛋白决定底物特异性。FBX 4和α B晶体蛋白的过表达触发了细胞周期蛋白D1的泛素化，并增加了细胞周期蛋白D1的周转。SCFFBX 4-alpha B晶体蛋白功能受损可减弱细胞周期蛋白D1的泛素化，促进细胞周期蛋白D1的过度表达，并加速细胞周期进程。纯化的SCFFBX 4-alpha B晶体蛋白体外催化细胞周期蛋白D1的多泛素化。与细胞周期蛋白D1 E3连接酶在肿瘤发生中的假定作用一致，在肿瘤衍生细胞系和过表达细胞周期蛋白D1的原发性人类癌症亚组中，FBX 4和α B晶体蛋白表达减少。我们得出结论，SCFFBX 4-α B晶体蛋白是一种E3泛素连接酶，促进Thr 286磷酸化细胞周期蛋白D1的泛素依赖性降解。
Growth factor-dependent accumulation of the cyclin D1 proto-oncogene is balanced by its rapid phosphorylation-dependent proteolysis. Degradation is triggered by threonine 286 phosphorylation, which promotes its ubiquitination by an unknown E3 ligase. We demonstrate that Thr286-phosphorylated cyclin D1 is recognized by a Skp1-Cul1-F box (SCF) ubiquitin ligase where FBX4 and alpha B crystallin govern substrate specificity. Overexpression of FBX4 and alpha B crystallin triggered cyclin D1 ubiquitination and increased cyclin D1 turnover. Impairment of SCFFBX4-alpha B crystallin function attenuated cyclin D1 ubiquitination, promoting cyclin D1 overexpression and accelerated cell-cycle progression. Purified SCFFBX4-alpha B crystallin catalyzed polyubiquitination of cyclin D1 in vitro. Consistent with a putative role for a cyclin D1 E3 ligase in tumorigenesis, FBX4 and alpha B crystallin expression was reduced in tumor-derived cell lines and a subset of primary human cancers that overexpress cyclin D1. We conclude that SCFFBX4-alpha B crystallin is an E3 ubiquitin ligase that promotes ubiquitin-dependent degradation of Thr286-phosphorylated cyclin D1.