MDMX overexpression prevents p53 activation by the MDM2 inhibitor nutlin
MDMX overexpression prevents p53 activation by the MDM2 inhibitor nutlin
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DOI：
10.1074/jbc.c600147200
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发表时间：
2006-11-03
影响因子：
4.8
通讯作者：
Chen, Jiandong
中科院分区：
文献类型：
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作者：
Hu, Baoli;Gilkes, Daniele M.;Chen, Jiandong
p53肿瘤抑制因子在维持基因组稳定性和防止恶性转化中起关键作用。MDM 2和MDMX都是调节p53稳定性和活性的p53结合蛋白。最近开发的MDM 2抑制剂Nutlin 3极大地促进了MDM 2-p53结合的功能分析。我们发现，虽然MDMX与MDM 2同源并结合于p53 N末端的相同区域，但Nutlin不破坏p53-MDMX相互作用。Nutlin激活p53的能力在过表达MDMX的肿瘤细胞中受到损害。Nutlin与MDMX siRNA的组合导致p53的协同活化和生长停滞。这些结果表明，MDMX也是肿瘤细胞中p53激活的有效靶标。开发MDMX特异性的或针对MDM 2和MDMX的双重抑制而优化的新型化合物对于实现肿瘤细胞中p53的完全活化是必要的。
The p53 tumor suppressor plays a key role in maintaining genomic stability and protection against malignant transformation. MDM2 and MDMX are both p53-binding proteins that regulate p53 stability and activity. Recent development of the MDM2 inhibitor Nutlin 3 has greatly facilitated functional analysis of MDM2-p53 binding. We found that although MDMX is homologous to MDM2 and binds to the same region on p53 N terminus, Nutlin does not disrupt p53-MDMX interaction. The ability of Nutlin to activate p53 is compromised in tumor cells overexpressing MDMX. Combination of Nutlin with MDMX siRNA resulted in synergistic activation of p53 and growth arrest. These results suggest that MDMX is also a valid target for p53 activation in tumor cells. Development of novel compounds that are MDMX-specific or optimized for dual-inhibition of MDM2 and MDMX are necessary to achieve full activation of p53 in tumor cells.