Pin1 dysregulation helps to explain the inverse association between cancer and Alzheimer's disease.
Pin1 dysregulation helps to explain the inverse association between cancer and Alzheimer's disease.
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DOI：
10.1016/j.bbagen.2014.12.025
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发表时间：
2015-10
影响因子：
3
通讯作者：
Lu, Kun Ping
中科院分区：
文献类型：
--
作者：
Driver, Jane A.;Zhou, Xiao Zhen;Lu, Kun Ping
Pin 1是一种细胞内信号分子，在阿尔茨海默病（AD）和许多人类癌症的发病机制中起着关键但相反的作用。我们回顾了Pin 1酶的结构和功能，它在循环细胞和神经元中发挥的不同作用，癌症和AD之间负相关的流行病学证据，以及基于Pin 1的疗法的潜在治疗意义。Pin 1是一种独特的酶，通过将靶蛋白“扭曲”成不同的形状来影响靶蛋白的功能。循环细胞使用Pin 1来帮助协调细胞分裂。它在许多常见的人类癌症中过表达和/或被多种机制激活，并作用于多种信号通路以促进肿瘤发生。在动物模型中抑制Pin 1具有显著的抗肿瘤作用。相比之下，Pin 1在AD大脑中通过多种机制下调或失活。Pin 1的缺失会损害tau功能和淀粉样蛋白前体蛋白加工，导致缠结和淀粉样蛋白相关的病理学以及与年龄相关的神经退行性变，类似于人类AD。我们已经开发了顺式和反式构象特异性抗体，以提供第一个直接证据，即tau以不同的顺式和反式构象存在，Pin 1加速其顺式到反式的转换，从而防止AD中的缠结形成。现有的Pin 1研究表明，癌症和AD可能有着共同的生物学途径，这些途径在不同的方向上被解除管制。Pin 1生物学为癌症和神经退行性变开辟了令人兴奋的预防和治疗视野。
Pin1 is an intracellular signaling molecule which plays a critical but opposite role in the pathogenesis of Alzheimer’s disease (AD) and many human cancers. We review the structure and function of the Pin1 enzyme, the diverse roles it plays in cycling cells and neurons, the epidemiologic evidence for the inverse association between cancer and AD, and the potential therapeutic implications of Pin1-based therapies. Pin1 is a unique enzyme that has effects the function of target proteins by “twisting” them into different shapes. Cycling cells use Pin1 to help coordinate cell division. It is over-expressed and/or activated by multiple mechanisms in many common human cancers, and acts on multiple signal pathways to promote tumorigenesis. Inhibition of Pin1 in animal models has profound anti-tumor effects. In contrast, Pin1 is down-regulated or inactivated by multiple mechanisms in AD brains. The absence of Pin1 impairs tau function and amyloid precursor protein processing, leading to tangle- and amyloid-related pathologies and neurodegeneration in an age-dependent manner, resembling human AD. We have developed cis and trans conformation-specific antibodies to provide the first direct evidence that tau exists in distinct cis and trans conformations and that Pin1 accelerates its cis to trans conversion, thereby protecting against tangle formation in AD. Available studies on Pin1 suggest that cancer and AD may share biological pathways that are deregulated in different directions. Pin1 biology opens exciting preventive and therapeutic horizons for both cancer and neurodegeneration.
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