Time course comparison of cell-cycle protein expression following partial hepatectomy and WY14,643-induced hepatic cell proliferation in F344 rats

• Published in: Carcinogenesis (New York) Vol. 18; no. 5; pp. 935 - 941
• Main Authors: RININGER, J. A, GOLDSWORTHY, T. L, BABISH, J. G
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.05.1997
• Subjects: Animal tumors. Experimental tumors; Animals; Biological and medical sciences; CDC2 Protein Kinase; CDC2-CDC28 Kinases; Cell Cycle; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 5; Cyclin-Dependent Kinases - metabolism; Cyclins - metabolism; Experimental digestive system and abdominal tumors; Genes, Tumor Suppressor; Hepatectomy; Liver Regeneration - drug effects; Male; Medical sciences; Microbodies - drug effects; Proliferating Cell Nuclear Antigen - metabolism; Protein-Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins; Pyrimidines - pharmacology; Rats; Rats, Inbred F344; Time Factors; Tumors; Cell proliferation; Rat; Enzyme; Transferases; Liver; Rodentia; Cyclin; Hepatectomy; Carcinogen; Signal transduction; Vertebrata; Experimental disease; Mammalia; Kinase; Animal; Cell cycle; Epigenetics; Mechanical stimulus; Mechanism of action; PCNA antigen; Chemical stimulus
• ISSN: 0143-3334; 1460-2180; 1460-2180
• DOI: 10.1093/carcin/18.5.935

During recent years, there has been an extensive research focus in the area of cell-cycle control in eukaryotes and the relationship that exists between cell proliferation and cancer. The eukaryotic cell-cycle is governed by signal transduction pathways mediated by complexes of cyclin dependent kinases (CDK) and their partner cyclin proteins. This study was performed to identify differences in cell-cycle control protein expression following physical and chemical stimuli of hepatic cell growth. Protein levels of cell cycle mediators, cyclin dependent kinases (CDK 1,2,4,5), cyclin proteins (A,B,D1-D3 and E), proliferating cell nuclear antigen (PCNA), tumor suppressor proteins (p53 and Rb), and CDK inhibitory proteins (p16Ink4, p21Waf1 and p27Kip1) were examined in F344 rats following 70% partial hepatectomy or a single dose of WY14,643 over 96- and 48-h time courses, respectively. CDK1 (p34cdc2) and PCNA protein concentrations, quantified by ELISA, were significantly increased beginning at the 24-h time point and maximal at 48 h (6.9- and 3.7-fold for partial hepatectomy and 4.2- and 3.3-fold for WY14,643, respectively). Differential effects were observed with the G1 cell-cycle mediators CDK4, CDK5, and cyclin D3, p21Waf1 and p27Kip1 CDK inhibitory protein concentrations rose in accordance with the induction of DNA synthesis and histone H1 kinase activity. In addition, there were dramatic differences in p53 protein expression patterns following partial hepatectomy versus WY14,643 dosing. Because non-genotoxic hepatocarcinogens are known to induce cellular proliferation, data generated from this study may aid in elucidating the specific hepatocarcinogenic signal transduction pathways stimulated by non-genotoxic carcinogens.