Sherr Charles J
Howard Hughes Medical Institute, Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Wiley Interdiscip Rev Dev Biol. 2012 Sep-Oct;1(5):731-41. doi: 10.1002/wdev.40.
Three tumor suppressor genes at the small (<50 kb) INK4-ARF (CDKN2A/B) locus on human chromosome 9p21 coordinate a signaling network that depends on the activities of the retinoblastoma (RB) protein and the p53 transcription factor. Disruption of this circuitry, frequently by codeletion of INK4-ARF, is a hallmark of cancer, begging the question of why the intimate genetic linkage of these tumor suppressor genes has been maintained in mammals despite the risk of their coinactivation. The INK4-ARF locus is not highly expressed under normal physiologic conditions in young mammals, but its induction becomes more pronounced as animals age. Notably, INK4-ARF is actively silenced en bloc in embryonic, fetal, and adult stem cells but becomes poised to respond to oncogenic stress signals as stem cells lose their self-renewal capacity and differentiate, thereby providing a potent barrier to tumor formation. Epigenetic remodeling of the locus as a whole provides a mechanism for coordinating the activities of RB and p53. A hypothesis is that the INK4-ARF locus may have evolved to physiologically restrict the self-renewal capacities and numbers of stem and progenitor cells with the attendant consequence of limiting tissue regenerative capacity, particularly as animals age. Deletion of INK4-ARF contributes to the aberrant self-renewal capacity of tumor cells and occurs frequently in many forms of human cancer.
人类9号染色体短臂（<50 kb）上的INK4-ARF（CDKN2A/B）基因座中有三个肿瘤抑制基因，它们共同协调一个依赖于视网膜母细胞瘤（RB）蛋白和p53转录因子活性的信号网络。该信号通路的破坏，通常是由于INK4-ARF的共同缺失，是癌症的一个标志，这就引出了一个问题：尽管这些肿瘤抑制基因存在共同失活的风险，但它们在哺乳动物中紧密的遗传联系为何得以维持。在年轻哺乳动物的正常生理条件下，INK4-ARF基因座的表达并不高，但随着动物年龄的增长，其诱导作用会变得更加明显。值得注意的是，INK4-ARF在胚胎、胎儿和成体干细胞中整体处于活跃沉默状态，但随着干细胞失去自我更新能力并分化，它会随时准备对致癌应激信号做出反应，从而为肿瘤形成提供了一个强大的屏障。整个基因座的表观遗传重塑为协调RB和p53的活性提供了一种机制。一种假说认为，INK4-ARF基因座可能已经进化到在生理上限制干细胞和祖细胞的自我更新能力和数量，其附带结果是限制组织再生能力，尤其是随着动物年龄的增长。INK4-ARF的缺失导致肿瘤细胞异常的自我更新能力，并且在许多人类癌症形式中频繁发生。
