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Regulation of polyamine metabolism and retinoblastoma protein phosphorylation by cytokines in cultured rat hepatocytes



Regulation of polyamine metabolism and retinoblastoma protein phosphorylation by cytokines in cultured rat hepatocytes



Journal of the Osaka City Medical Center 48(3-4): 287-296



Hepatocyte proliferation in regenerating liver is regulated by cytokines such as hepatocyte growth factor (HGF), transforming growth factor-alpha (TGF- alpha), and transforming growth factor-beta 1 (TGF-beta 1). In this study, I examined the effects of cytokines on polyamine metabolism and on phosphorylation of retinoblastoma protein (pRb) in cultured rat hepatocytes. Primary hepatocytes (2.0 X 104 cells / 0.2 ml / cm2) were incubated in William's medium E containing fetal bovine serum for 6 h and for 18 h more without serum. This was 0 h, at which time, cytokine or polyamine was added. alpha-difluoromethylornithine, an ornithine decarboxylase (ODC) inhibitor, was added imediately after older medium was replaced with fresh medium. TGF-alpha increased ODC activity up to 12 h after it was added, but TGF-beta1 did not. ODC activity and S-adenosylmethionine decarboxylase activity was increased by HGF for 6 h after it was added, and these were more increased by TGF-alpha added at the same time. TGF-beta 1 inhibited the increase in the activity of ODC caused by HGF, but did not in the activity of the S-adenosylmethionine decarboxylase. The higher cellular concentration of hepatocytes was, the more the increase in ODC activity was inhibited. These findings suggested that changes in the polyamines level caused by changes in ODC activity affect the hepatocyte proliferation. ODC mRNA expression was not changed for the first 6 h after HGF and TGF-beta 1 were added. pRb expression and phosphorylation were higher, starting at 12 h after HGF was added. alpha-difluoromethylornithine inhibited the phosphorylation of pRb, and each polyamines prevented this inhibition. From these results, in the early phase of proliferation of hepatocytes when a cytekine is added, ODC activity is increased by post-transcriptional regulation, and polyamines may bring about pRb phosphorylation, resulting in progression of the cells to the S phase.

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