Mutations in human ARF exon 2 disrupt its nucleolar localization and impair its ability to block nuclear export of MDM2 and p53
Mutations in human ARF exon 2 disrupt its nucleolar localization and impair its ability to block nuclear export of MDM2 and p53
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DOI：
10.1016/s1097-2765(00)80351-2
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发表时间：
1999-05-01
期刊：
影响因子：
16
通讯作者：
Xiong, Y
中科院分区：
文献类型：
--
作者：
Zhang, YP;Xiong, Y
哺乳动物ARF-INK 4a基因座通过使用单独的启动子和替代性阅读框而独特地编码两种细胞周期抑制剂，p16（INK 4a）维持视网膜母细胞瘤蛋白处于其生长抑制状态，而ARF稳定p53。我们报告，人类ARF蛋白主要定位于核仁内的外显子2编码的C-末端结构域的序列，并诱导离开核仁的MDM 2。ARF与MDM 2和p53形成核小体，并阻断p53和MDM 2的核输出。ARF外显子2的肿瘤相关突变破坏了ARF的核仁定位，降低了ARF阻断p53核输出和稳定p53的能力。我们的研究结果表明，ARF调节MDM 2依赖的p53稳定和连接的人类肿瘤相关的突变ARF与功能的改变。
The mammalian ARF-INK4a locus uniquely encodes two cell cycle inhibitors by using separate promoters and alternative reading frames, p16(INK4a) maintains the retinoblastoma protein in its growth suppressive state while ARF stabilizes p53. We report that human ARF protein predominantly localizes to the nucleolus via a sequence within the exon 2-encoded C-terminal domain and is induced to leave the nucleolus by MDM2. ARF forms nuclear bodies with MDM2 and p53 and blocks p53 and MDM2 nuclear export. Tumor-associated mutations in ARF exon 2 disrupt ARF's nucleolus localization and reduce ARF's ability to block p53 nuclear export and to stabilize p53. Our results suggest an ARF-regulated MDM2-dependent p53 stabilization and link the human tumor-associated mutations in ARF with a functional alteration.