p19ARF directly and differentially controls the functions of c-Myc independently of p53
p19ARF directly and differentially controls the functions of c-Myc independently of p53
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DOI：
10.1038/nature02958
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发表时间：
2004-10-07
期刊：
影响因子：
64.8
通讯作者：
Hann, SR
中科院分区：
文献类型：
--
作者：
Qi, Y;Gregory, MA;Hann, SR
致癌转录因子c-Myc的表达增加导致细胞周期进程不受调节(1)。c-Myc也能引起细胞凋亡，但尚不清楚c-Myc靶基因的激活和/或抑制是否介导了c-Myc的这些不同功能。由于不受控制的细胞周期进程导致过度增殖和肿瘤发生，肿瘤抑制因子，如p53和p19(ARF) (ARF)，在c-Myc增加时抑制细胞周期进程是必不可少的（文献2,3）。c-Myc的增加已经被证明可以诱导ARF表达，从而通过激活p53导致细胞周期阻滞或凋亡（文献4）。本研究表明，ARF可以通过一种独立于p53的独特而直接的机制抑制c-Myc。当c-Myc增加时，ARF与c-Myc结合并显著阻断c-Myc激活转录和诱导过度增殖和转化的能力。相反，c-Myc抑制转录的能力不受ARF的影响，c-Myc介导的细胞凋亡增强。ARF对c-Myc功能的不同影响表明，不同的分子机制介导了c-Myc诱导的过度增殖和凋亡。这种直接反馈机制代表了一种p53独立检查点来防止c- myc介导的肿瘤发生。
Increased expression of the oncogenic transcription factor c-Myc causes unregulated cell cycle progression(1). c-Myc can also cause apoptosis, but it is not known whether the activation and/or repression of c-Myc target genes mediates these diverse functions of c-Myc. Because unchecked cell cycle progression leads to hyperproliferation and tumorigenesis, it is essential for tumour suppressors, such as p53 and p19(ARF) (ARF), to curb cell cycle progression in response to increased c-Myc (refs 2, 3). Increased c-Myc has previously been shown to induce ARF expression, which leads to cell cycle arrest or apoptosis through the activation of p53 (ref. 4). Here we show that ARF can inhibit c-Myc by a unique and direct mechanism that is independent of p53. When c-Myc increases, ARF binds with c-Myc and dramatically blocks c-Myc's ability to activate transcription and induce hyperproliferation and transformation. In contrast, c-Myc's ability to repress transcription is unaffected by ARF and c-Myc-mediated apoptosis is enhanced. These differential effects of ARF on c-Myc function suggest that separate molecular mechanisms mediate c-Myc-induced hyperproliferation and apoptosis. This direct feedback mechanism represents a p53-independent checkpoint to prevent c-Myc-mediated tumorigenesis.