Human tumor suppressor ARF impedes S-phase progression independent of p53.
Human tumor suppressor ARF impedes S-phase progression independent of p53.
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发表时间：
2002-02
期刊：
影响因子：
11.2
通讯作者：
W. Yarbrough;M. Bessho;A. Zanation;J. Bisi;Y. Xiong
中科院分区：
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作者：
W. Yarbrough;M. Bessho;A. Zanation;J. Bisi;Y. Xiong
使用替代性阅读框架，人ARF-INK 4a基因座编码两种不相关的蛋白质，这两种蛋白质都在肿瘤抑制中起作用。p16（INK 4a）通过抑制细胞周期蛋白D依赖性激酶活性维持视网膜母细胞瘤蛋白的生长抑制状态，而ARF与MDM 2结合并稳定p53。迄今为止，ARF的大部分活性归因于其激活p53的能力，导致G（1）细胞周期停滞或凋亡。我们发现ARF与DNA复制蛋白A（RPA 32）共定位，并且ARF的过度表达降低了DNA合成的速率，导致S期细胞群的积累。ARF对DNA合成的阻碍可能会发生，并且在p53缺失的情况下变得更加明显。因此，ARF诱导的生物学后果依赖于细胞p53状态而变化，主要诱导p53阳性细胞中的G（1）停滞或凋亡，或者当p53功能被破坏时引起S期阻滞。
Using alternative reading frames, the human ARF-INK4a locus encodes two unrelated proteins that both function in tumor suppression. p16(INK4a) maintains the retinoblastoma protein in its growth-suppressive state through inhibition of cyclin D-dependent kinase activity, whereas ARF binds with MDM2 and stabilizes p53. The majority of the activity of ARF to date is ascribed to its ability to activate p53, resulting in a G(1) cell cycle arrest or apoptosis. We show here that ARF colocalizes with DNA replication protein A (RPA32) and that overexpression of ARF reduces the rate of DNA synthesis resulting in accumulation of an S-phase cell population. Impediment of DNA synthesis by ARF can occur and becomes more evident in the absence of p53. Hence, the biological consequence of ARF induction varies dependent on cellular p53 status, inducing predominantly a G(1) arrest or apoptosis in p53-positive cells or causing S-phase retardation when p53 function is comprised.