Levels of HdmX expression dictate the sensitivity of normal and transformed cells to nutlin-3
Levels of HdmX expression dictate the sensitivity of normal and transformed cells to nutlin-3
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DOI：
10.1158/0008-5472.can-05-3832
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发表时间：
2006-03-15
期刊：
影响因子：
11.2
通讯作者：
Jackson, MW
中科院分区：
文献类型：
--
作者：
Patton, JT;Mayo, LD;Jackson, MW
Hdm 2和HdmX协同调节p53的稳定性和功能。每一种都在许多不同类型的恶性肿瘤的亚群中过表达，并且这些亚群中的大多数维持野生型p53。Nutlins是一种新发现的Hdm 2-p53相互作用的小分子抑制剂，为野生型p53肿瘤的治疗提供了一种新的策略。我们现在表明，Nutlin-3有效地诱导细胞凋亡，并减少了在体外由Hdm 2而不是HdmX转化的人成纤维细胞的Iona期存活。过表达HdmX的细胞对Nutlin-3的抗性是由于其不能破坏p53-HdmX相互作用，导致p53活性的持续抑制。尽管HdmX过表达产生了对Nutlin-3具有抗性的细胞，但通过短发夹RNA消除HdmX表达使肿瘤细胞对Nutlin-3介导的细胞死亡或停滞敏感。此外，删除COOH-末端的环指结构域的HdmX完全逆转的耐药性Nutlin-3，可能反映了与Hdm 2相互作用的环指的要求。因此，Hdm 2和HdmX的相对丰度和Nutlin-3对Hdm 2的特异性影响细胞对响应于Nutlin-3的p53依赖性凋亡或停滞的敏感性。我们的研究结果确立了Hdm 2和HdmX作为重新激活野生型p53作为癌症治疗手段的独立治疗靶点。
Hdm2 and HdmX coordinately regulate the stability and function of p53. Each is overexpressed in subsets of many different types of malignancy, and most of these subsets maintain wild-type p53. Nutlins, newly discovered small-molecude inhibitors of the Hdm2-p53 interaction, offer a novel strategy for therapy of tumors with wild-type p53. We now show that Nutlin-3 efficiently induces apoptosis and diminishes Iona-term survival of human fibroblasts transformed in vitro by Hdm2 but not HdmX. The resistance of cells overexpressing HdmX to Nutlin-3 is due to its inability to disrupt the p53-HdmX interaction, resulting in continued suppression of p53 activity. Although HdmX overexpression yielded cells resistant to Nutlin-3, ablation of HdmX expression by short hairpin RNA sensitized tumor cells to Nutlin-3-mediated cell death or arrest. Furthermore, deletion of the COOH-terminal RING finger domain of HdmX completely reversed the resistance to Nutlin-3, probably reflecting the requirement of the RING finger for interaction with Hdm2. Thus, the relative abundance of Hdm2 and HdmX and the specificity of Nutlin-3 for Hdm2 influence the sensitivity of cells to p53-dependent apoptosis or arrest in response to Nutlin-3. Our findings establish Hdm2 and HdmX as independent therapeutic targets with respect to reactivating wild-type p53 as a means for cancer therapy.