Disturbances in hepatic cell-cycle regulation in mice with assembly-deficient keratins 8/18

Simple epithelial tissues such as liver and pancreas express keratins 8 (K8 ) and 18 (K18) as their major intermediate filament proteins. K8 and K18 nu ll mice and transgenic mice that express mutant K18 (K18C) manifest several hepatocyte abnormalities and demonstrate that K8/18 are important in maint aining liver tissue and cell integrity, although other potential functions remain uncharacterized. Here, we report an additional abnormal liver phenot ype, which is similar in K8 null, K18 null, and K18C mouse models. Liver hi stologic examination showed large polynuclear areas that lacked cell membra nes, desmosomal structures, and filamentous actin. Similar, but less promin ent, areas were observed in the pancreas. The parenchyma outside the polynu clear areas displayed irregular sinusoidal structures and markedly enlarged nuclei. Most K8 null hepatocytes were positive for the proliferating cell nuclear antigen (PCNA) with a doubled DNA content in comparison with the pr edominantly PCNA-negative wild-type hepatocytes. The distribution of the 14 -3-3 zeta protein was also altered in K8 null mice. Taken together, our res ults indicate that absence of keratin filaments causes disturbances in cell -cycle regulation, driving cells into the S-G2 phase and causing aberrant c ytokinesis. These effects could stem from disturbed functions of KS/18-depe ndent cell-cycle regulators, such as the signaling integrator, 14-3-3.