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Disturbances in hepatic cell‐cycle regulation in mice with assembly‐deficient keratins 8/18
Author(s) -
Toivola Diana M.,
Nieminen Mikko I.,
Hesse Michael,
He Tao,
Baribault Hélène,
Magin Thomas M.,
Omary M. Bishr,
Eriksson John E.
Publication year - 2001
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1053/jhep.2001.29374
Subject(s) - proliferating cell nuclear antigen , keratin , biology , microbiology and biotechnology , cell cycle , null cell , intermediate filament , cytokinesis , keratin 8 , cell , cytoskeleton , cell growth , cell division , cell culture , genetics
Simple epithelial tissues such as liver and pancreas express keratins 8 (K8) and 18 (K18) as their major intermediate filament proteins. K8 and K1 null mice and transgenic mice that express mutant K18 (K18C) manifest several hepatocyte abnormalities and demonstrate that K8/18 are important in maintaining liver tissue and cell integrity, although other potential functions remain uncharacterized. Here, we report an additional abnormal liver phenotype, which is similar in K8 null, K18 null, and K18C mouse models. Liver histologic examination showed large polynuclear areas that lacked cell membranes, desmosomal structures, and filamentous actin. Similar, but less prominent, areas were observed in the pancreas. The parenchyma outside the polynuclear 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 predominantly PCNA‐negative wild‐type hepatocytes. The distribution of the 14‐3‐3ζ protein was also altered in K8 null mice. Taken together, our results indicate that absence of keratin filaments causes disturbances in cell‐cycle regulation, driving cells into the S‐G2 phase and causing aberrant cytokinesis. These effects could stem from disturbed functions of K8/18‐dependent cell‐cycle regulators, such as the signaling integrator, 14‐3‐3.