Swierenga S H, Marceau N, Katsuma Y, French S W, Mueller R, Lee F
Drugs Directorate, Health and Welfare, Canada, Ottawa.
Cell Biol Toxicol. 1989 Nov;5(3):271-86. doi: 10.1007/BF01795356.
Rat liver T51B cells were maintained in the presence of low concentrations of Ni(II) derived from alpha Ni3S2 for 3-15 months in culture in order to monitor cytokeratin, differentiation, and transformation patterns. Nickel exposures caused irreversible, heritable juxtanuclear aggregates of cytokeratin CK55, which increased in size and complexity with prolonged nickel exposure, eventually resembling Mallory bodies and expressing glutamyltransferase. Altered cytokeratin expression was accompanied by induction of differentiation, with markers of both bile ductular cells and hepatocytes, such as induction of cytokeratin polypeptides CK39 and CK49, cell morphology, and cytokeratin filament network changes; whereas control cultures similarly maintained for long periods in culture remained unchanged. Altered cytokeratin expression was also accompanied by acquisition of transformation markers--loss of density dependence, progression toward calcium independence, and (benign) growth in nude mice. Observed cytokeratin aberrations may be a factor in nickel carcinogenesis, in view of the known affinity of the metal for cellular structural proteins, especially keratin, which play a role in maintenance of cell behavior.
为监测细胞角蛋白、分化和转化模式，将大鼠肝T51B细胞在含有低浓度源自α-Ni3S2的Ni(II)的条件下培养3至15个月。镍暴露导致细胞角蛋白CK55形成不可逆的、可遗传的近核聚集物，随着镍暴露时间延长，其大小和复杂性增加，最终类似马洛里小体并表达谷氨酰转移酶。细胞角蛋白表达改变伴随着分化诱导，出现胆管细胞和肝细胞的标志物，如细胞角蛋白多肽CK39和CK49的诱导、细胞形态以及细胞角蛋白丝网络变化；而同样在培养中长期维持的对照培养物则保持不变。细胞角蛋白表达改变还伴随着转化标志物的获得——密度依赖性丧失、向钙非依赖性进展以及在裸鼠体内（良性）生长。鉴于该金属对细胞结构蛋白尤其是角蛋白具有已知亲和力，而角蛋白在维持细胞行为中起作用，所观察到的细胞角蛋白异常可能是镍致癌的一个因素。
