锌Metallochaperones突变型p53反应器:癌症治疗的一种新范式。
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Kogan年代,Carpizo博士
锌Metallochaperones突变型p53反应器:癌症治疗的一种新范式。
癌症(巴塞尔)。2018年5月29日,10 (6)。pii: cancers10060166。doi: 10.3390 / cancers10060166。
- PubMed ID
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29843463 (在PubMed]
- 文摘
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恢复野生型p53突变体的结构和功能小分子(以下称为“重新激活”p53突变)是一个圣杯的癌症疗法。大多数TP53突变是错义生成缺陷蛋白通道。我们正在开发一个新的突变型p53反应器称为锌metallochaperones (ZMCs),在这里,我们回顾我们当前的理解他们。p53蛋白需要绑定一个锌离子,协调四个氨基酸的DNA结合域,为适当的结构和功能。野生型结构的损失损害锌钝化p53的绑定是一种常见的机制。ZMCs激活p53突变使用小说由两部分组成的机制,包括恢复野生型结构重建锌绑定和激活p53通过转录后修饰诱导细胞活性氧(ROS)。前者导致野生型构象改变,后来引发p53-mediated凋亡程序来杀死癌细胞。ZMCs小分子金属离子螯合剂结合锌和其他二价金属离子强大到足以把锌从血清白蛋白,但疲软足以捐给p53突变。最近我们扩展机制的理解ZMCs锌的作用细胞的反应。我们发现细胞锌体内平衡机制,通常函数保持自由picomolar中细胞内锌含量范围,由ZMCs诱导。 By normalizing zinc levels, they function as an OFF switch to ZMCs because zinc levels are no longer sufficiently high to maintain a wild-type structure. This on/off switch leads to a transient nature to the mechanism of ZMCs in which mutant p53 activity comes on in a few hours and then is turned off. This finding has important implications for the translation of ZMCs to the clinic because it indicates that ZMC concentrations need not be maintained at high levels for their activity. Indeed, we found that short exposures (as little as 15 min) were adequate to observe the mutant p53 reactivating activity. This switch mechanism imparts an advantage over other targeted therapeutics in that efficacy can be accomplished with minimal exposure which minimizes toxicity and maximizes the therapeutic window. This on/off switch mechanism is unique in targeted cancer therapeutics and will impact the design of human clinical trials.