MIT的研究人员发现在小鼠模式中，将p53的功能恢复后，竟能使肿瘤萎缩或消失，此研究成果发表于1月24日的Nature期刊。显示p53应可用作为人类抗癌药的潜力股。Dr. David Kirsch表示：假如能筛选到癌细胞中使p53功能恢复的化合物，将可阻断癌细胞的生长。
p53长期以来就在癌症的形成中扮演关键的角色，人类的癌症中，有50%都是由于p53基因突变或蛋白质表现异常所致。在正常细胞里p53能控制细胞周期(cell cycle)的进行，调控基因的表现，避免受损的DNA复制及促进细胞自然凋亡等功能，当p53突变或异常而失去功能，细胞就会不受控制而产生癌化现象。
研究中利用RNAi的方法将小鼠的p53基因静默，使小鼠产生肿瘤，再利用基因工程的技术将p53的功能恢复，发现肿瘤缩小的范围从40%~100%不等，目前研究人员也已经筛出一些化合物，能促进p53的功能复原，在小鼠模式中明显可见肿瘤的体积缩小，有些肿瘤还完全消失。在淋巴瘤(cancer-lymphomas)细胞中，p53活性恢复后的1~2天内，癌细胞就开始进入自然凋亡(apoptosis)的过程，但在肉瘤(sarcomas)细胞中，却不走自然凋亡的路径，反而是让癌细胞自然老化不再生长，目前，研究人员尚不清楚为何不同的癌细胞会走不同的死亡路径。
在一连串的试验中，确定p53的活性复原并不会对细胞造成任何的毒副作用，意即可以设计药物来复原癌细胞内的p53活性，目前nutlins是最具潜力的药物，它是MDM2的抑制剂，能解除MDM2对p53蛋白表现的抑制，使p53的活性恢复。 (资料来源 : Bio.com)
部分英文原文：
Restoration of p53 function leads to tumour regression in vivo
Andrea Ventura1,5, David G. Kirsch1,2,5, Margaret E. McLaughlin1, David A. Tuveson1, Jan Grimm3, Laura Lintault1, Jamie Newman1, Elizabeth E. Reczek1, Ralph Weissleder3 and Tyler Jacks1,4
Tumorigenesis is a multi-step process that requires activation of oncogenes and inactivation of tumour suppressor genes1. Mouse models of human cancers have recently demonstrated that continuous expression of a dominantly acting oncogene (for example, Hras, Kras and Myc) is often required for tumour maintenance2, 3, 4, 5; this phenotype is referred to as oncogene addiction6. This concept has received clinical validation by the development of active anticancer drugs that specifically inhibit the function of oncoproteins such as BCR-ABL, c-KIT and EGFR7, 8, 9, 10. Identifying additional gene mutations that are required for tumour maintenance may therefore yield clinically useful targets for new cancer therapies. Although loss of p53 function is a common feature of human cancers11, it is not known whether sustained inactivation of this or other tumour suppressor pathways is required for tumour maintenance. To explore this issue, we developed a Cre-loxP-based strategy to temporally control tumour suppressor gene expression in vivo. Here we show that restoring endogenous p53 expression leads to regression of autochthonous lymphomas and sarcomas in mice without affecting normal tissues. The mechanism responsible for tumour regression is dependent on the tumour type, with the main consequence of p53 restoration being apoptosis in lymphomas and suppression of cell growth with features of cellular senescence in sarcomas. These results support efforts to treat human cancers by way of pharmacological reactivation of p53.
相关报道:
Gene&Dev：肿瘤抑制蛋白p53存在多种构象
突变的MYC可使肿瘤细胞逃过p53的监控网络
Cancer Research：中南大学肿瘤研究所等发表p53新发现
p53 阻止肿瘤血液供给
p53抑制肿瘤的新途径
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