Khan Abid, Shover Wesley, Goodliffe Julie M
Department of Biology, The University of North Carolina, Charlotte, NC, USA.
PLoS One. 2009;4(3):e5076. doi: 10.1371/journal.pone.0005076. Epub 2009 Mar 31.
All tumor cell lines that have been tested are defective for Myc auto-repression, and have high levels of Myc produced from wild type loci and re-arranged loci. Like mammalian Myc auto-repression, Myc protein represses the expression of its gene, dmyc, in Drosophila. This activity requires Polycomb (Pc), since RNAi for Pc in the embryo eliminates Myc auto-repression. We have observed that upon depletion of Polycomb in the embryo, levels of one of 18 different chromatin-binding genetic regulators, Su(z)2, rise dramatically. We pursued the possibility that increased levels of this protein, Su(z)2, interfere with Myc auto-repression, potentially explaining the loss of auto-repression upon Pc RNAi. We report that embryos expressing both ectopic Myc and ectopic Su(z)2 fail in Myc auto-repression. Surprisingly, histone H3K27 tri-methylation at the dmyc locus is inversely correlated with the presence of auto-repression. We show phenotypic consequences of potent dmyc auto-repression, and their complete reversal by ectopic Su(z)2: dmyc auto-repression induced a diminutive (dm) phenotype, and upon elimination of auto-repression by Su(z)2, overall levels of Myc increased and completely rescued the phenotype. We show that this increase in Myc levels caused dramatic activation of Myc activation targets. These data suggest that Su(z)2 is capable of increasing the potency of Myc activity by eliminating Myc's feedback regulation by auto-repression. Although Su(z)2 eliminated Myc auto-repression, we found that Myc repression of other genes is not affected by Su(z)2. These data suggest a unique antagonistic role for Su(z)2 in Myc auto-repression, and a potential mechanism for cancer-cell specific loss of Myc auto-repression.
所有经过测试的肿瘤细胞系在Myc自我抑制方面均存在缺陷，并且从野生型位点和重排位点产生的Myc水平很高。与哺乳动物的Myc自我抑制一样，Myc蛋白在果蝇中抑制其基因dmyc的表达。这种活性需要多梳蛋白（Pc），因为胚胎中针对Pc的RNA干扰消除了Myc自我抑制。我们观察到，在胚胎中多梳蛋白缺失后，18种不同的染色质结合基因调节因子之一的Su(z)2水平会急剧上升。我们探讨了这种蛋白Su(z)2水平升高会干扰Myc自我抑制的可能性，这可能解释了Pc RNA干扰后自我抑制的丧失。我们报告称，同时表达异位Myc和异位Su(z)2的胚胎在Myc自我抑制方面失败。令人惊讶的是，dmyc基因座处的组蛋白H3K27三甲基化与自我抑制的存在呈负相关。我们展示了强效dmyc自我抑制的表型后果，以及异位Su(z)2对其的完全逆转：dmyc自我抑制诱导了侏儒（dm）表型，而通过Su(z)2消除自我抑制后，Myc的总体水平增加并完全挽救了该表型。我们表明，Myc水平的这种增加导致了Myc激活靶点的显著激活。这些数据表明，Su(z)2能够通过消除Myc的自我抑制反馈调节来增强Myc活性的效力。尽管Su(z)2消除了Myc自我抑制，但我们发现Myc对其他基因的抑制不受Su(z)2影响。这些数据表明Su(z)2在Myc自我抑制中具有独特的拮抗作用，以及癌细胞特异性丧失Myc自我抑制的潜在机制。
