Soussi Thierry, Hjortsberg Linn
Department of Oncology-Pathology, Cancer Centre Karolinska (CCK), Karolinska Institute, SE-171 76 Stockholm, Sweden.
Trends Mol Med. 2009 Jan;15(1):1-4. doi: 10.1016/j.molmed.2008.11.002. Epub 2008 Dec 25.
p53 missense mutations observed in human cancers are often associated with an increased level of p53 protein in the tumour. Using mouse models, Terzian et al. recently showed that this accumulation of mutant p53 protein is not associated with specific properties of the protein itself but instead depends on the endogenous genetic background of the tumours and on two important genes, mouse double minute 2 (Mdm2) and the cyclin kinase inhibitor p16INK4a. Mice expressing mutant p53 in the absence of Mdm2 display more aggressive metastatic tumours. In light of these observations, targeting the MDM2-p53 interaction for therapy of human cancer could be more complicated than previously anticipated.
在人类癌症中观察到的p53错义突变通常与肿瘤中p53蛋白水平升高有关。使用小鼠模型，特尔齐安等人最近表明，突变型p53蛋白的这种积累与蛋白质本身的特定特性无关，而是取决于肿瘤的内源性遗传背景以及两个重要基因，即小鼠双微体2（Mdm2）和细胞周期蛋白激酶抑制剂p16INK4a。在没有Mdm2的情况下表达突变型p53的小鼠表现出更具侵袭性的转移性肿瘤。鉴于这些观察结果，针对MDM2-p53相互作用进行人类癌症治疗可能比先前预期的更为复杂。
