Tumor suppressor ARF degrades B23, a nucleolar protein involved in ribosome biogenesis and cell proliferation
Tumor suppressor ARF degrades B23, a nucleolar protein involved in ribosome biogenesis and cell proliferation
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DOI：
10.1016/s1097-2765(03)00431-3
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发表时间：
2003-11-01
期刊：
影响因子：
16
通讯作者：
Zhang, YP
中科院分区：
文献类型：
--
作者：
Itahana, K;Bhat, KP;Zhang, YP
肿瘤抑制因子ARF诱导p53依赖性和非依赖性细胞周期阻滞。与核质MDM2和p53不同，ARF定位于核仁。ARF在核仁中的作用、分子靶点及其不依赖p53的功能机制尚不清楚。本研究表明，ARF与参与核糖体生物发生的多功能核蛋白B23相互作用，并促进其多泛素化和降解。在正常成纤维细胞中，过表达B23诱导细胞周期阻滞，而在缺乏p53的细胞中，它促进S期进入。相反，敲低B23会抑制核糖体前RNA的加工并诱导细胞死亡。此外，致癌Ras仅在ARF缺失的细胞中诱导B23，而在保留野生型ARF的细胞中则不诱导。总之，我们的研究结果揭示了ARF通过抑制B23调节核糖体生物发生和细胞增殖的分子机制，并表明ARF在监测致癌损伤中的核仁作用。
The tumor suppressor ARF induces a p53-dependent and -independent cell cycle arrest. Unlike the nucleoplasmic MDM2 and p53, ARF localizes in the nucleolus. The role of ARF in the nucleolus, the molecular target, and the mechanism of its p53-independent function remains unclear. Here we show that ARF interacts with B23, a multifunctional nucleolar protein involved in ribosome biogenesis, and promotes its polyubiquitination and degradation. Overexpression of B23 induces a cell cycle arrest in normal fibroblasts, whereas in cells lacking p53 it promotes S phase entry. Conversely, knocking down B23 inhibits the processing of preribosomal RNA and induces cell death. Further, oncogenic Ras induces B23 only in ARF null cells, but not in cells that retain wild-type ARF. Together, our results reveal a molecular mechanism of ARF in regulating ribosome biogenesis and cell proliferation via inhibiting B23, and suggest a nucleolar role of ARF in surveillance of oncogenic insults.