Alteration of differentiation state of human hepatocytes cultured with novobiocin and butyrate.
Chang liver cells cultured in the simultaneous presence of novobiocin and butyrate stopped proliferating and changed into fibroblast-like cells with remarkably elongated cytoplasm. In these fibroblast-like cells, the cellular content of both protein and DNA was increased 2- to 3-fold. In addition, the production of specific proteins such as type III procollagen, actin, and tubulin was increased and the expression of proliferation-associated nuclear antigen which was reactive with Ki-67 monoclonal antibody was reduced remarkably. Therefore, Chang liver cells cultured with novobiocin and butyrate were considered to be arrested at the premitotic G2 phase of the cell cycle and then enter into the noncycling resting state. These actions of novobiocin and butyrate were not mediated by the pathway of epidermal growth factor action or modulated by the diacylglycerol agonist 1-oleoyl-2-acetylglycerol and the C kinase inhibitor 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine. On the other hand, novobiocin was disclosed to be a stimulator of [3H]acetate uptake and acted synergistically with butyrate in enhancing nuclear protein acetylation. From these results it can be speculated that novobiocin and butyrate chemically modulate nuclear proteins and thereby alter the gene expression and the differentiation state of Chang liver cells.
Kaneko
Y
Y
First Department of Medicine, University of Tokyo, Japan.
Nakayama
T
T
Tsukamoto
A
A
Kurokawa
K
K
D000107:Acetylation; D015153:Blotting, Western; D002087:Butyrates / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000166:cytology*; D008113:Liver Neoplasms / Q000473:pathology*; D008970:Molecular Weight; D009675:Novobiocin / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen; D014407:Tumor Cells, Cultured
D002087:Butyrates; D009687:Nuclear Proteins; D018809:Proliferating Cell Nuclear Antigen; D009675:Novobiocin; D004815:Epidermal Growth Factor; D003094:Collagen