Zhang Y, Xiong Y
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill 27599, USA.
Mol Cell. 1999 May;3(5):579-91. doi: 10.1016/s1097-2765(00)80351-2.
The mammalian ARF-INK4a locus uniquely encodes two cell cycle inhibitors by using separate promoters and alternative reading frames. p16INK4a 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.
哺乳动物的ARF-INK4a基因座通过使用不同的启动子和可变阅读框独特地编码两种细胞周期抑制剂。p16INK4a将视网膜母细胞瘤蛋白维持在其生长抑制状态，而ARF则使p53稳定。我们报告，人类ARF蛋白主要通过外显子2编码的C末端结构域内的一个序列定位于核仁，并被MDM2诱导离开核仁。ARF与MDM2和p53形成核体，并阻止p53和MDM2的核输出。ARF外显子2中的肿瘤相关突变破坏了ARF的核仁定位，并降低了ARF阻止p53核输出和稳定p53的能力。我们的结果提示了一种由ARF调节的、依赖MDM2的p53稳定机制，并将人类ARF中的肿瘤相关突变与功能改变联系起来。
