A non-tumor suppressor role for basal p19ARF in maintaining nucleolar structure and function
A non-tumor suppressor role for basal p19ARF in maintaining nucleolar structure and function
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DOI：
10.1128/mcb.00484-07
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发表时间：
2008-02-01
影响因子：
5.3
通讯作者：
Weber, Jason D.
中科院分区：
文献类型：
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作者：
Apicelli, Anthony J.;Maggi, Leonard B., Jr.;Weber, Jason D.
核仁是核糖体合成的中心，核磷蛋白（NPM）和P19（ARF）蛋白相互拮抗，促进或抑制生长。然而，基础NPM和ARF蛋白形成核仁复合物，其功能尚不清楚。Arf（-/-）细胞的核仁面积增加，提示基底Arf可能调节关键的核仁功能。同时，在缺乏Arf的情况下，核糖体的生物发生和蛋白质合成急剧增加，导致这些细胞在蛋白质含量和细胞体积上表现出巨大的增加。在没有ARF的情况下，核糖体DNA （rDNA）的转录、新生rRNA分子的加工和核糖体的核输出都增加了。在野生型mef中使用靶向慢病毒RNA干扰ARF获得了类似的结果。ARF缺失小鼠的有丝分裂后破骨细胞在体外和体内表现出高活性，证明了基础ARF的生理功能。此外，NPM的敲低阻断了Arf（-/-）核糖体输出和破骨细胞活性的增加，表明这些增益需要NPM。因此，基础ARE蛋白作为稳定状态核糖体生物发生和生长的监测器，独立于它们防止不必要的过度增殖的能力。
The nucleolus is the center of ribosome synthesis, with the nucleophosmin (NPM) and P19(ARF) proteins antagonizing one another to either promote or inhibit growth. However, basal NPM and ARF proteins form nucleolar complexes whose functions remain unknown. Nucleoli from Arf(-/-) cells displayed increased nucleolar area, suggesting that basal ARF might regulate key nucleolar functions. Concordantly, ribosome biogenesis and protein synthesis were dramatically elevated in the absence of Arf, causing these cells to exhibit tremendous gains in protein amounts and increases in cell volume. The transcription of ribosomal DNA (rDNA), the processing of nascent rRNA molecules, and the nuclear export of ribosomes were all increased in the absence of ARF. Similar results were obtained using targeted lentiviral RNA interference of ARF in wild-type MEFs. Postmitotic osteoclasts from Arf-null mice exhibited hyperactivity in vitro and in vivo, demonstrating a physiological function for basal ARF. Moreover, the knockdown of NPM blocked the increases in Arf(-/-) ribosome output and osteoclast activity, demonstrating that these gains require NPM. Thus, basal ARE proteins act as a monitor of steady-state ribosome biogenesis and growth independent of their ability to prevent unwarranted hyperproliferation.