Kamijo T, van de Kamp E, Chong M J, Zindy F, Diehl J A, Sherr C J, McKinnon P J
Howard Hughes Medical Institute, and Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Cancer Res. 1999 May 15;59(10):2464-9.
The alternative reading frame product (p19ARF) of the mouse INK4a/ARF locus is induced by oncoproteins such as Myc and E1A as part of a checkpoint response that limits cell cycle progression in response to hyperproliferative signals. ARF binds directly to Mdm2 to prevent down-regulation of p53 and thereby promotes p53-dependent transcription and cell cycle arrest. However, ARF is not required for p53 induction in response to ionizing radiation or other forms of DNA damage. Animals lacking a functional ataxia telangiectasia (Atm) gene are exquisitely sensitive to ionizing radiation; Atm-null mouse embryo fibroblasts (MEFs) undergo premature replicative arrest, which is relieved by the loss of p53. Here we show that the loss of ARF expands the life expectancy of Atm-null MEFs, but alters neither the sensitivity of Atm-null mice to ionizing radiation nor their propensity to develop lymphomas early in life. Therefore, whereas ARF and Atm signal to p53 through distinct pathways, the loss of ARF can modify p53-dependent features of the Atm-null phenotype.
小鼠INK4a/ARF基因座的可变阅读框产物（p19ARF）由Myc和E1A等癌蛋白诱导产生，作为一种检查点反应的一部分，该反应会响应过度增殖信号限制细胞周期进程。ARF直接与Mdm2结合，以防止p53下调，从而促进p53依赖的转录和细胞周期停滞。然而，在响应电离辐射或其他形式的DNA损伤时，诱导p53并不需要ARF。缺乏功能性共济失调毛细血管扩张症（Atm）基因的动物对电离辐射极为敏感；Atm基因缺失的小鼠胚胎成纤维细胞（MEF）会过早发生复制性停滞，而p53缺失可缓解这种停滞。在此我们表明，ARF缺失可延长Atm基因缺失的MEF的寿命，但既不改变Atm基因缺失小鼠对电离辐射的敏感性，也不改变它们在生命早期发生淋巴瘤的倾向。因此，尽管ARF和Atm通过不同途径向p53发出信号，但ARF缺失可改变Atm基因缺失表型中依赖p53的特征。
