PDF(Pubmed)
Abstract：
Amplification of MDM2 on supernumerary chromosomes is a common mechanism of P53 inactivation across tumors. Here, we investigated the impact of MDM2 overexpression on chromatin, gene expression, and cellular phenotypes in liposarcoma. Three independent regulatory circuits predominate in aggressive, dedifferentiated tumors. RUNX and AP-1 family transcription factors bind mesenchymal gene enhancers. P53 and MDM2 co-occupy enhancers and promoters associated with P53 signaling. When highly expressed, MDM2 also binds thousands of P53-independent growth and stress response genes, whose promoters engage in multi-way topological interactions. Overexpressed MDM2 concentrates within nuclear foci that co-localize with PML and YY1 and could also contribute to P53-independent phenotypes associated with supraphysiologic MDM2. Importantly, we observe striking cell-to-cell variability in MDM2 copy number and expression in tumors and models. Whereas liposarcoma cells are generally sensitive to MDM2 inhibitors and their combination with pro-apoptotic drugs, MDM2-high cells tolerate them and may underlie the poor clinical efficacy of these agents.
摘要：
多个染色体上MDM2的扩增是跨肿瘤的P53失活的常见机制。这里,我们调查了MDM2过表达对染色质的影响，基因表达，和脂肪肉瘤的细胞表型。三个独立的监管电路在侵略性中占主导地位，去分化肿瘤。RUNX和AP-1家族转录因子结合间充质基因增强子。P53和MDM2共同占据与P53信号传导相关的增强子和启动子。当高度表达时，MDM2还结合了数千个P53非依赖性生长和应激反应基因，其启动子参与多路拓扑相互作用。过表达的MDM2集中在与PML和YY1共定位的核病灶内，也可能导致与超生理MDM2相关的不依赖P53的表型。重要的是,我们观察到肿瘤和模型中MDM2拷贝数和表达的惊人的细胞间变异性.而脂肪肉瘤细胞通常对MDM2抑制剂及其与促凋亡药物的组合敏感，高MDM2细胞耐受它们，可能是这些药物临床疗效差的基础。
