Residues in the alternative reading frame tumor suppressor that influence its stability and p53-independent activities.
Residues in the alternative reading frame tumor suppressor that influence its stability and p53-independent activities.
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DOI：
10.1016/j.yexcr.2009.01.010
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发表时间：
2009-04-15
影响因子：
3.7
通讯作者：
Quelle DE
中科院分区：
文献类型：
--
作者：
di Tommaso A;Hagen J;Tompkins V;Muniz V;Dudakovic A;Kitzis A;Ladeveze V;Quelle DE
替代阅读框架（ARF）蛋白通过p53依赖性和p53非依赖性途径抑制肿瘤发生。ARF的大部分抗增殖活性是由其第一个外显子中的序列赋予的。先前的工作表明，在灵长类进化过程中，该区域发生了特定的氨基酸变化，因此我们将这些变化编程到人类p14 ARF中，以测定其功能影响。发现两个人p14 ARF残基（Ala 14和Thr 31）使蛋白质不稳定，而另外两个残基（Val 24和Ala 41）促进更有效的p53稳定和活化。尽管有这些作用，所有修饰的p14 ARF形式都显示出强有力的p53依赖性抗增殖活性，证明在与猿和人p14 ARF残基相关的p53介导的生长抑制中没有显著的生物学差异。与此相反，p53-独立的p14 ARF功能大大改变了几个残基的变化。Val 24是p53非依赖性生长抑制所必需的，而多个残基（Val 24、Thr 31、Ala 41和His 60）使p14 ARF能够阻断或逆转p53无效MEF的固有染色体不稳定性。总之，这些数据确定了特定的残基以外的既定p14 ARF功能域，影响其表达和信号转导活动。最有趣的是，这项工作揭示了一个新的和直接的作用，p14 ARF在p53-独立的基因组稳定性的维护。
The Alternative Reading Frame (ARF) protein suppresses tumorigenesis through p53-dependent and p53-independent pathways. Most of ARF’s anti-proliferative activity is conferred by sequences in its first exon. Previous work showed specific amino acid changes occurred in that region during primate evolution, so we programmed those changes into human p14ARF to assay their functional impact. Two human p14ARF residues (Ala14 and Thr31) were found to destabilize the protein while two others (Val24 and Ala41) promoted more efficient p53 stabilization and activation. Despite those effects, all modified p14ARF forms displayed robust p53-dependent anti-proliferative activity demonstrating there are no significant biological differences in p53-mediated growth suppression associated with simian versus human p14ARF residues. In contrast, p53-independent p14ARF function was considerably altered by several residue changes. Val24 was required for p53-independent growth suppression whereas multiple residues (Val24, Thr31, Ala41 and His60) enabled p14ARF to block or reverse the inherent chromosomal instability of p53-null MEFs. Together, these data pinpoint specific residues outside of established p14ARF functional domains that influence its expression and signaling activities. Most intriguingly, this work reveals a novel and direct role for p14ARF in the p53-independent maintenance of genomic stability.
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