Pin1 dysregulation helps to explain the inverse association between cancer and Alzheimer's disease

• Published in: Biochimica et biophysica acta 2015-10, Vol.1850 (10), p.2069-2076
• Main Authors: Driver, Jane A., Zhou, Xiao Zhen, Lu, Kun Ping
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - therapy; Alzheimer's disease; Amyloid - genetics; Amyloid - metabolism; Animals; Cancer; Humans; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - therapy; NIMA-Interacting Peptidylprolyl Isomerase; Peptidylprolyl Isomerase - genetics; Peptidylprolyl Isomerase - metabolism; Phosphorylation signaling; Pin1; Signal Transduction; tau Proteins - genetics; tau Proteins - metabolism
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2014.12.025

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 on 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. This article is part of a Special Issue entitled Proline-directed Foldases: Cell Signaling Catalysts and Drug Targets. •Pin1 regulates the function of a subset of phosphoproteins by catalyzing cis–trans isomerization.•Pin1 is activated and thereby promotes tumorigenesis by turning on multiple cancer pathways.•Pin1 inhibition leads to the buildup of the abnormal cis-conformation of tau and APP, thereby promoting Alzheimer's disease.•Pin1 opens exciting preventive and therapeutic horizons for both cancer and neurodegeneration.