Abstract
Hepatopoietin (HPO) is a novel human hepatotrophic growth factor, which specifically stimulates proliferation of cultured primary hepatocytes in vitro and liver regeneration after liver partial hepatectomy in vivo. Recently, the identification of the mitogenic effect of HPO on hepatoma cell lines and the existence of HPO-specific receptors indicate that HPO acts via its specific cell surface receptor. However, the molecular mechanism of HPO action is not fully elucidated. In this report, we examined the signal transduction events induced by HPO in hepatoma cell line (HepG2). Our results demonstrated that HPO induces phosphorylation of mitogen-activated protein kinase kinase and mitogen-activated protein kinase (MAPK) in a rapid and transient manner. HPO stimulates tyrosine phosphorylation of epidermal growth factor receptor (EGFR). Furthermore, we observed that both MAPK activation and the mitogenic effect of HPO on HepG2 cells were completely blocked by AG1478, a specific inhibitor of EGFR tyrosine kinase activity. However, the effects of HPO were not antagonized by an EGFR-blocking antibody, mAb528, which blocks the interaction between epidermal growth factor and EGFR, indicating that stimulation of tyrosine phosphorylation of EGFR by HPO was not mediated by epidermal growth factor. In contrast, genistein, a general tyrosine kinase inhibitor, significantly attenuated the tyrosine phosphorylation of EGFR in response to HPO. In conclusion, our results suggest that tyrosine phosphorylation of EGFR may play a critical role in MAPK activation and mitogenic stimulation by HPO.
Highlights
Hepatopoietin (HPO)1 is a novel human hepatotrophic growth factor, an orthologue of rat augmenter of liver regener
Our results show that mAb528 had no effect on the tyrosine phosphorylation of epidermal growth factor receptor (EGFR) triggered by HPO, it completely blocked the tyrosine phosphorylation triggered by epidermal growth factor (EGF) (Fig. 6)
The role of HPO as a stimulator of hepatocyte proliferation in liver regeneration has been systematically investigated since the 1970s, the molecular mechanisms of HPO action are unclear
Summary
Hepatopoietin (HPO) is a novel human hepatotrophic growth factor, an orthologue of rat augmenter of liver regener-. Yang et al [8,9] demonstrated that the recombinant human HPO stimulated proliferation of hepatocytes as well as hepatoma cells in vitro. HPO promotes regeneration and recovery of damaged hepatocytes and rescues acute hepatic failure in vivo [8, 9] These observations support the contention that HPO is a hepatotrophic growth factor. HPO stimulates proliferation of cultured primary hepatocytes in vitro and enhances liver regeneration after liver partial hepatectomy in vivo. HPO displays no significant effect on the proliferation of non-hepatocytes or tumor cell lines derived from tissues other than liver [10]. We showed that HPO acts as an autocrine growth factor to maintain the autonomous growth of hepatoma cell lines in vitro These findings suggest that HPO binds a specific receptor. Considering the importance of the mitogen-activated protein kinase (MAPK) pathway in cell growth, we investigated activation of the MAPK pathway by HPO
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