MDM2 oncogene as a novel target for human cancer therapy.
MDM2 oncogene as a novel target for human cancer therapy.
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DOI：
10.2174/1381612003400911
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发表时间：
2000-02
影响因子：
3.1
通讯作者：
Ruiwen Zhang;Hui Wang
中科院分区：
文献类型：
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作者：
Ruiwen Zhang;Hui Wang
MDM2致癌基因首先在小鼠3T3DM细胞系（一种自发转化的BALB/c 3T3细胞衍生物）的双分钟染色体上被克隆。MDM2致癌基因现已被证明在许多人类癌症中被扩增或过度表达。也有研究表明，MDM2水平与几种人类癌症的不良预后有关。最令人兴奋的发现是MDM2-p53自我调节反馈回路，它调节p53肿瘤抑制基因的功能。MDM2基因是p53直接转录激活的靶标，而MDM2蛋白是p53的负调控因子。MDM2癌蛋白与p53蛋白结合，抑制p53作为转录因子的功能，诱导p53降解。p53肿瘤抑制因子在癌症治疗中发挥着重要作用，p53介导的细胞生长阻滞和/或凋亡是许多临床使用的癌症化疗药物和放射治疗的主要作用机制。因此，MDM2-p53相互作用可能是癌症治疗的靶点。此外，MDM2对p53的负调控可能会限制DNA损伤剂对p53的激活程度，从而限制其治疗效果。如果MDM2对p53的反馈抑制被中断，功能p53水平的显著增加将增加p53介导的治疗效果。目前已经使用这种策略测试了几种方法，包括针对MDM2-p53结合域的多肽和特异性抑制MDM2表达的反义寡核苷酸。除了与p53相互作用外，MDM2蛋白还被发现与其他细胞蛋白如pRb和E2F-1相互作用。尽管这些相互作用的确切功能和意义尚不完全清楚，但MDM2不依赖于p53的功能可能在癌症的病因和进展中发挥作用，这表明MDM2癌基因是癌症治疗的潜在分子靶点。
The MDM2 oncogene was first cloned as an amplified gene on a murine double-minute chromosome in the 3T3DM cell line, a spontaneously transformed derivative of BALB/c 3T3 cells. The MDM2 oncogene has now been shown to be amplified or overexpressed in many human cancers. It also has been suggested that MDM2 levels are associated with poor prognosis of several human cancers. The most exciting finding is the MDM2-p53 autoregulatory feedback loop that regulates the function of the p53 tumor suppressor gene. The MDM2 gene is a target for direct transcriptional activation by p53, and the MDM2 protein is a negative regulator of p53. The MDM2 oncoprotein binds to the p53 protein, inhibiting p53 functions as a transcription factor and inducing p53 degradation. The p53 tumor suppressor has an important role in cancer therapy, with p53-mediated cell growth arrest and/or apoptosis being major mechanisms of action for many clinically used cancer chemotherapeutic agents and radiation therapy. Therefore, the MDM2-p53 interaction may be a target for cancer therapy. In addition, the negative regulation of p53 by MDM2 may limit the magnitude of p53 activation by DNA damaging agents, thereby limiting their therapeutic effectiveness. If the MDM2 feed-back inhibition of p53 is interrupted, a significant increase in functional p53 levels will increase p53-mediated therapeutic effectiveness. Several approaches have now been tested using this strategy, including polypeptides targeted to MDM2-p53 binding domain and antisense oligonucleotides that specifically inhibit MDM2 expression. In addition to the interaction with p53, the MDM2 protein has been found to have interactions with other cellular proteins such as pRb and E2F-1. Although the exact function and significance of these interactions are not fully understood, the p53-independent functions of MDM2 may have a role in cancer etiology and progression, indicating that the MDM2 oncogene is a potential molecular target for cancer therapy.