The tumor suppressor ING3 is degraded by SCFSkp2-mediated ubiquitin-proteasome system
The tumor suppressor ING3 is degraded by SCFSkp2-mediated ubiquitin-proteasome system
复制标题
DOI：
10.1038/onc.2009.424
复制
发表时间：
2010-03-01
期刊：
影响因子：
8
通讯作者：
Li, G.
中科院分区：
文献类型：
--
作者：
Chen, G.;Wang, Y.;Li, G.
生长抑制因子家族成员3（ING 3）已被证明可以调节转录、细胞周期控制和凋亡。我们先前报道了黑色素瘤细胞核ING 3表达显著降低，这与患者生存率较差相关，表明ING 3表达降低可能与黑色素瘤进展相关。然而，黑色素瘤中ING 3表达减少的机制尚不清楚。在这里，我们表明ING 3水平在转移性黑色素瘤细胞中由于快速降解而降低。此外，我们发现ING 3通过泛素蛋白酶体途径降解。ING 3与E3连接酶Skp 1-Cullin-F-box蛋白复合物（SCF复合物）的亚基物理相互作用。F-box蛋白S期激酶相关蛋白2（Skp 2）的敲低降低了黑色素瘤细胞中ING 3的泛素化，并显着稳定ING 3。此外，赖氨酸96残基对于ING 3泛素化是必需的，因为其突变为精氨酸显著地消除了ING 3降解。破坏ING 3降解刺激ING 3诱导的G1期细胞周期阻滞和增强紫外线诱导的细胞凋亡。总之，我们的数据表明，ING 3通过泛素-蛋白酶体途径通过SCFSkp 2复合物降解，并且ING 3降解的中断增强了ING 3的肿瘤抑制功能，这通过干扰ING 3降解提供了潜在的癌症治疗方法。Oncogene（2010）29，1498-1508; doi：10.1038/onc.2009.424; 2009年11月23日在线发表
The inhibitor of growth family member 3 (ING3) has been shown to modulate transcription, cell cycle control and apoptosis. We previously reported that nuclear ING3 expression was remarkably reduced in melanomas, which correlated with a poorer patient survival, suggesting that decreased ING3 expression may be associated with melanoma progression. However, the mechanism of diminished ING3 expression in melanoma is not clear. Here we show that ING3 level was decreased in metastatic melanoma cells because of a rapid degradation. Furthermore, we showed that ING3 undergoes degradation through the ubiquitin proteasome pathway. ING3 physically interacts with subunits of E3 ligase Skp1-Cullin-F-box protein complex (SCF complex). Knockdown of F-box protein S-phase kinase-associated protein 2 (Skp2) reduces the ubiquitination of ING3 and significantly stabilizes ING3 in melanoma cells. In addition, lysine 96 residue is essential for ING3 ubiquitination as its mutation to arginine dramatically abrogated ING3 degradation. Disruption of ING3 degradation stimulated ING3-induced G1 cell-cycle arrest and enhanced ultraviolet-induced apoptosis. Taken together, our data show that ING3 is degraded by the ubiquitin-proteasome pathway through the SCFSkp2 complex and interruption of ING3 degradation enhances the tumor-suppressive function of ING3, which provides a potential cancer therapeutic approach by interfering ING3 degradation. Oncogene (2010) 29, 1498-1508; doi:10.1038/onc.2009.424; published online 23 November 2009