Induction of p53-dependent p21 limits proliferative activity of rat hepatocytes in the presence of hepatocyte growth factor

• Published in: PloS one Vol. 8; no. 11; p. e78346
• Main Authors: Inoue, Yukiko, Tomiya, Tomoaki, Nishikawa, Takako, Ohtomo, Natsuko, Tanoue, Yasushi, Ikeda, Hitoshi, Koike, Kazuhiko
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 04-11-2013; Public Library of Science (PLoS)
• Subjects: Animal tissues; Animals; Antisense DNA; Antisense oligonucleotides; Apoptosis; Cell Count; Cell cycle; Cell division; Cell growth; Cell Proliferation; Chemical synthesis; Cyclin-dependent kinase inhibitor p21; Cyclin-Dependent Kinase Inhibitor p21 - antagonists & inhibitors; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Density; Deoxyribonucleic acid; DNA; DNA - biosynthesis; DNA damage; DNA synthesis; Fibroblasts; Gastroenterology; Gene expression; Gene Expression Regulation; Growth factors; Hepatectomy; Hepatitis; Hepatocyte growth factor; Hepatocyte Growth Factor - pharmacology; Hepatocytes; Hepatocytes - cytology; Hepatocytes - drug effects; Hepatocytes - metabolism; Kinases; Liver; Liver - cytology; Liver - drug effects; Liver - metabolism; Male; Medicine; Mitogens; p53 Protein; Physiological aspects; Physiological effects; Primary Cell Culture; Proteins; Rats; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Rodents; Signal Transduction; Tumor proteins; Tumor Suppressor Protein p53 - antagonists & inhibitors; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Japan; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0078346

Hepatocyte growth factor (HGF), a potent mitogen for hepatocytes, enhances hepatocyte function without stimulating proliferation, depending on the physiological conditions. p53, a transcription factor, suppresses the cell proliferation by expressing p21(WAF1/CIP1) in various tissues.
To investigate the mechanism through which the hepatocytes maintain mitotically quiescent even in the presence of HGF.
We studied the relationship between p53 and p21 expression and the effect of p53-p21 axis on hepatocyte proliferation in primary cultured rat hepatocytes stimulated by HGF. Hepatic p21 levels are determined serially after partial hepatectomy or sham operation in rats.
DNA synthesis was markedly increased by HGF addition in rat hepatocytes cultured at low density but not at high density. Cellular p53 levels increased in the hepatocytes cultured at both the densities. p21 levels were increased and correlated with cellular p53 levels in hepatocytes cultured at high density but not at low density. When the activity of p53 was suppressed by a chemical inhibitor for p53, cellular p21 levels were reduced, and DNA synthesis was increased. Similarly, p21 antisense oligonucleotide increased the DNA synthesis. In rats after partial hepatectomy, transient elevation of hepatic p21 levels was observed. In contrast, in sham-operated rats, hepatic p21 levels were increased on sustained time scales.
p53-related induction of p21 may suppress hepatocyte proliferation in the presence of HGF in the setting that mitogenic activity of HGF is not elicitable.