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Developmental strategies for evasion of Arf tumor suppression.

机译：逃避Arf肿瘤抑制的发展策略。

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Deletion of CDKN2A is a frequent event in human cancers. The locus specifies two tumor suppressor proteins, pl6~(INK4a) and pl4~(ARF) (p19~(ArF) in the mouse), encoded in part by alterative reading frames (from which ARF gets its name). The p16~(INK4a) polypeptide inhibits cyclin D-dependent kinases to maintain the retinoblastoma protein (RB) in its growth suppressive state, whereas pl4~(ARF) inhibits HDM2 (Mdm2 in the mouse) to trigger a p53 transcriptional response. Although point mutations inactivating pl6~(INK4A) can predispose to some familial cancers and occur frequently in many sporadic tumors, point mutations affecting pl4~(ARF) function are rare. Hence, ARF loss-of-function occurs when CDKN2A is deleted or silenced, events that frequently but not invariably affect both genes in the cluster. Some investigators interpreted these findings to mean that ARF inactivation might simply be a secondary consequence of selection for pl6~(INK4a) loss; moreover, even when Arf inactivation in the mouse revealed its potent p53-dependent tumor suppressive activity, others have continued to suggest that this might represent an artifact of mouse biology. By now, however, many cancer biologists have concluded that CDKN2A (an unfortunate misnomer) encodes two potent tumor suppressors (only one of which is a CDK inhibitor), and that deletion of the locus compromises both the RB and p53 pathways.1 Hyperproliferative signals resulting from oncogene activation (e.g., RAS mutation, MYC overexpression, BCR-ABL translocation) induce ARF expression, ultimately triggering p53-dependent cell cycle arrest or apoptosis in incipient cancer cells. However, oncogene signaling also provides the selective pressure for the outgrowth of cells that escape tumor suppression by inactivating CDKN2A. Recent work on T-cell acute lymphoblastic leukemia (T-ALL) underscores the importance of the developmental context of the cell targeted for oncogenic transformation in further determining functional relationships between these sentinel genetic events.
机译：CDKN2A的删除是人类癌症中的常见事件。该基因座指定了两种抑癌蛋白，p16〜（INK4a）和p14〜（ARF）（小鼠中的p19〜（ArF）），部分由可变阅读框编码（ARF以此命名）。 p16〜（INK4a）多肽抑制细胞周期蛋白D依赖性激酶，使视网膜母细胞瘤蛋白（RB）保持其生长抑制状态，而pl4〜（ARF）抑制HDM2（小鼠中的Mdm2）触发p53转录反应。尽管使p16〜（INK4A）失活的点突变可能易患某些家族性癌症，并在许多散发性肿瘤中频繁发生，但影响p14〜（ARF）功能的点突变却很少。因此，当删除或沉默CDKN2A时，会发生ARF功能丧失，这种事件经常但并非总是影响簇中的两个基因。一些研究人员将这些发现解释为意味着ARF失活可能只是选择pl6〜（INK4a）损失的次要结果。此外，即使Arf灭活小鼠显示出其强大的p53依赖性肿瘤抑制活性，也有其他人继续暗示这可能代表了小鼠生物学的假象。但是，到目前为止，许多癌症生物学家已经得出结论，CDKN2A（一种不幸的错误用语）编码了两种有效的肿瘤抑制因子（其中只有一种是CDK抑制剂），并且基因座的缺失会破坏RB和p53通路。1过度增殖信号由癌基因激活（例如，RAS突变，MYC过表达，BCR-ABL易位）引起的结果诱导ARF表达，最终触发了早期癌细胞中p53依赖性细胞周期停滞或凋亡。然而，癌基因信号传导也为通过灭活CDKN2A逃避肿瘤抑制的细胞的生长提供了选择压力。 T细胞急性淋巴细胞白血病（T-ALL）的最新工作强调了致癌转化靶细胞的发展背景在进一步确定这些前哨遗传事件之间的功能关系中的重要性。

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