P19ARF stabilizes p53 by blocking nucleo-cytoplasmic shuttling of Mdm2
P19ARF stabilizes p53 by blocking nucleo-cytoplasmic shuttling of Mdm2
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DOI：
10.1073/pnas.96.12.6937
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发表时间：
1999-06-08
影响因子：
11.1
通讯作者：
Levine, AJ
中科院分区：
文献类型：
--
作者：
Tao, WK;Levine, AJ
INK 4a-ARF基因座编码两种不同的肿瘤抑制因子，p16（INK 4a）和p19（ARF）。p16（INK 4a）通过阻止视网膜母细胞瘤蛋白的磷酸化来抑制细胞生长，而p19（ARF）通过减弱Mdm 2介导的p53降解来起作用，从而稳定p53。最近的数据表明，Mdm 2穿梭于细胞核和细胞质之间，并且Mdm 2的核质穿梭对于Mdm 2促进p53降解的能力是必不可少的。因此，Mdm 2必须将p53从细胞核输出到细胞质，在细胞质中它靶向p53进行降解。我们发现，p19（ARF）的共表达阻断了Mdm 2的核质穿梭，而且，Mdm 2的亚核定位以穿梭时间依赖的方式从核质到核仁发生变化，而p19（ARF）仅定位于核仁。在含有Mdm 2和p19（ARF）的异核体中，允许Mdm 2穿梭的时间越长，越多的Mdm 2蛋白与p19（ARF）在核仁中共定位，这意味着Mdm 2从核质移动到核仁，然后与核仁中的p19（ARF）缔合。这一观察结果表明，Mdm 2可能通过核仁输出，p19（ARF）可以通过将Mdm 2束缚在核仁中来抑制Mdm 2的核输出。总之，p19（ARF）可以通过抑制Mdm 2的核输出来稳定p53。
The INK4a-ARF locus encodes two distinct tumor suppressors, p16(INK4a) and p19(ARF). Whereas p16(INK4a) restrains cell growth through preventing phosphorylation of the retinoblastoma protein, p19(ARF) acts by attenuating Mdm2-mediated degradation of p53, thereby stabilizing p53. Recent data indicate that Mdm2 shuttles between the nucleus and the cytoplasm and that nucleo-cytoplasmic shuttling of Mdm2 is essential for Mdm2's ability to promote p53 degradation. Therefore, Mdm2 must export p53 from the nucleus to the cytoplasm where it targets p53 for degradation. We show here that coexpression of p19(ARF) blocks the nucleo-cytoplasmic shuttling of Mdm2, Moreover, subnuclear localization of Mdm2 changes from the nucleoplasm to the nucleolus in a shuttling time-dependent manner, whereas p19(ARF) is exclusively located in the nucleolus. In heterokaryons containing Mdm2 and p19(ARF), the longer the Mdm2 shuttling is allowed, the more Mdm2 protein colocalizes with p19(ARF) in the nucleolus, implying that Mdm2 moves from the nucleoplasm to the nucleolus and then associates with p19(ARF) there, Furthermore, whether or not Mdm2 colocalizes with p19(ARF) in the nucleolus, p19(ARF) prevents Mdm2 shuttling. This observation suggests that Mdm2 might be exported through the nucleolus and p19(ARF) could inhibit the nuclear export of Mdm2 by tethering Mdm2 in the nucleolus. Taken together, p19(ARF) could stabilize p53 by inhibiting the nuclear export of Mdm2.