Ku Nam-On, Michie Sara, Resurreccion Evelyn Z, Broome Rosemary L, Omary M Bishr
Department of Medicine, Veterans Affairs Palo Alto Health Care System, 3801 Miranda Avenue, 154J, Palo Alto, CA 94304, USA.
Proc Natl Acad Sci U S A. 2002 Apr 2;99(7):4373-8. doi: 10.1073/pnas.072624299. Epub 2002 Mar 26.
Keratin polypeptides 8 and 18 (K8/18) are the major intermediate filament proteins of simple-type epithelia. K18 Ser-33 phosphorylation regulates its binding to 14-3-3 proteins during mitosis. We studied the significance of keratin binding to 14-3-3 in transgenic mice that overexpress wild-type or Ser-33-->Ala (S33A) K18. In S33A but not wild-type K18-overexpressing mice, pancreatic acinar cell keratin filaments retracted from the basal nuclear region and became apically concentrated. In contrast, K18 S33A had a minimal effect on hepatocyte keratin filament organization. Partial hepatectomy of K18-S33A-overexpressing mice did not affect liver regeneration but caused limited mitotic arrest, accumulation of abnormal mitotic figures, dramatic fragmentation of hepatocyte keratin filaments, with retention of a speckled 14-3-3zeta mitotic cell nuclear-staining pattern that usually becomes diffuse during mitosis. Hence, K18 Ser-33 phosphorylation regulates keratin filament organization in simple-type epithelia in vivo. Keratin binding to 14-3-3 may partially modulate hepatocyte mitotic progression, in association with nuclear redistribution of 14-3-3 proteins during mitosis.
角蛋白多肽8和18（K8/18）是简单型上皮细胞的主要中间丝蛋白。K18丝氨酸33位点的磷酸化在有丝分裂期间调节其与14-3-3蛋白的结合。我们在过表达野生型或丝氨酸33突变为丙氨酸（S33A）的K18的转基因小鼠中研究了角蛋白与14-3-3结合的意义。在过表达S33A而非野生型K18的小鼠中，胰腺腺泡细胞角蛋白丝从基底核区域缩回并在顶端聚集。相比之下，K18 S33A对肝细胞角蛋白丝的组织影响极小。对过表达K18-S33A的小鼠进行部分肝切除并不影响肝脏再生，但会导致有限的有丝分裂停滞、异常有丝分裂图像的积累、肝细胞角蛋白丝的显著断裂，并保留一种斑点状的14-3-3ζ有丝分裂细胞核染色模式，这种模式在有丝分裂期间通常会变得弥散。因此，K18丝氨酸33位点的磷酸化在体内调节简单型上皮细胞中的角蛋白丝组织。角蛋白与14-3-3的结合可能部分调节肝细胞有丝分裂进程，这与有丝分裂期间14-3-3蛋白的核重新分布有关。
