Dm. Toivola et al., Disturbances in hepatic cell-cycle regulation in mice with assembly-deficient keratins 8/18, HEPATOLOGY, 34(6), 2001, pp. 1174-1183
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.