2008年来自Dartmouth医学院的Sarah Thompson和DuaneCompton发现，大部分的染色体不稳定状态下的细胞与错误的染色体着丝粒和有丝分裂纺锤体有关联。正常的细胞在染色体异常分配下会停止有丝分裂，而肿瘤细胞中的异倍体却不会停止有丝分裂，这是什么原因？
Sarah研究小组为了追踪这一真相，通过人工改造人类细胞，在染色体上加上荧光蛋白标记，这样可以观察有丝分裂中这些细胞染色体的分配过程。
他们人为地诱导细胞有丝分裂染色体异常分配，并通过荧光标记来区分正常和异常的细胞，结果发现，正常情况下异倍体的细胞停止分裂。在这些停止分裂的细胞中，发现p53以及相关转录产物p21表达量异常高。原文检索：Transcription-independent ARF regulation in oncogenicstress-mediated p53 responsesThe tumour suppressor ARF is specifically required for p53activation under oncogenic stress1, 2, 3, 4, 5, 6. Recent studiesshowed that p53 activation mediated by ARF, but not that induced byDNA damage, acts as a major protection against tumorigenesis invivo under certain biological settings7, 8, suggesting that theARF–p53 axis has more fundamental functions in tumour suppressionthan originally thought. Because ARF is a very stable protein inmost human cell lines, it has been widely assumed that ARFinduction is mediated mainly at the transcriptional level and thatactivation of the ARF–p53 pathway by oncogenes is a much slower andlargely irreversible process by comparison with p53 activationafter DNA damage. Here we report that ARF is very unstable innormal human cells but that its degradation is inhibited incancerous cells. Through biochemical purification, we identified aspecific ubiquitin ligase for ARF and named it ULF. ULF interactswith ARF both in vitro and in vivo and promotes thelysine-independent ubiquitylation and degradation of ARF. ULFknockdown stabilizes ARF in normal human cells, triggeringARF-dependent, p53-mediated growth arrest. Moreover, nucleophosmin(NPM) and c-Myc, both of which are commonly overexpressed in cancercells, are capable of abrogating ULF-mediated ARF ubiquitylationthrough distinct mechanisms, and thereby promote ARF stabilizationin cancer cells. These findings reveal the dynamic feature of theARF–p53 pathway and suggest that transcription-independentmechanisms are critically involved in ARF regulation duringresponses to oncogenic stress.