Pin1: a new genetic link between Alzheimer's disease, cancer and aging.
Pin1: a new genetic link between Alzheimer's disease, cancer and aging.
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DOI：
10.2174/1874609811003030158
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发表时间：
2010-11
影响因子：
--
通讯作者：
J. Driver;K. Lu
中科院分区：
文献类型：
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作者：
J. Driver;K. Lu
流行病学数据表明，患有神经退行性疾病的人患癌症的风险较低。这很耐人寻味，因为越来越多的证据表明，神经退化和癌症发生共享许多生物学途径，例如异常进入细胞周期。独特的酶Pin1在阿尔茨海默病和许多人类癌症的发病机制中发挥着关键作用。Pin1在特定位置被磷酸化后作用于蛋白质，导致它们在两个完全不同的构象之间扭曲。这种构象变化深刻地影响着蛋白质的活性，是细胞信号和调节的主要方法。在神经元中，Pin1通过将磷酸化的tau和淀粉样前体蛋白恢复到功能状态来促进细胞健康。活性PIN1的丧失导致异常的tau堆积和β-淀粉样蛋白的过度生产，这是阿尔茨海默病的主要特征。Pin1还调节细胞周期，是细胞分裂所必需的酶。Pin1的过表达可通过多种信号通路促进肿瘤的发生。我们假设Pin1可能有助于解释阿尔茨海默病和癌症之间的反向关系。小鼠缺乏Pin1会导致早期衰老表型，这表明Pin1活性对于健康衰老和预防与年龄相关的疾病是必要的。我们综述了Pin1在癌症和神经退行性变中的作用，讨论了Pin1与衰老的关系，并探索了其作为诊断和治疗靶点的潜力。
Epidemiologic data suggest that people who develop neurodegenerative diseases of aging have a decreased risk of cancer. This is intriguing, since there is growing evidence that neurodegeneration and carcinogenesis share a number of biological pathways, such as abnormal entry into the cell cycle. The unique enzyme Pin1 plays a key role in the pathogenesis of Alzheimer's disease and many human cancers. Pin1 acts on proteins after they have been phosphorylated at specific sites, causing them to twist between two completely distinct conformations. This conformational change profoundly affects protein activity and is a major method of cellular signaling and regulation. In the neuron, Pin1 promotes cellular health by restoring phosphorylated tau and amyloid precursor protein to a functional state. The loss of active Pin1 leads to the accumulation of abnormal tau and the overproduction of β-amyloid, the cardinal features of Alzheimer's disease. Pin1 also regulates the cell cycle and is a necessary enzyme for cell division. Over-expression of Pin1 can promote oncogenesis through a number of signaling pathways. We hypothesize that Pin1 might help explain an inverse relationship between Alzheimer's disease and cancer. Pin1 deficiency in mice leads to an early-aging phenotype, suggesting that Pin1 activity is necessary for healthy aging and the prevention of age-related diseases. We review the role of Pin1 in cancer and neurodegeneration, discuss the relationship between Pin1 and aging, and explore its potential as a diagnostic and therapeutic target.