Journal Article

Induction of DNA synthesis in primary mouse hepatocytes is associated with nuclear pro-transforming growth factor α and erbb-1 and is independent of c-jun

Elisabeth Schausberger, Robert Eferl, Wolfram Parzefall, Monica Chabikovsky, Paul Breit, Erwin F. Wagner, Rolf Schulte-Hermann and Bettina Grasl-Kraupp

in Carcinogenesis

Volume 24, issue 5, pages 835-841
Published in print May 2003 | ISSN: 0143-3334
Published online May 2003 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgg027
Induction of DNA synthesis in primary mouse hepatocytes is associated with nuclear pro-transforming growth factor α and erbb-1 and is independent of c-jun

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For growth stimulation of liver cells by hepatocyte growth factor (HGF) or transforming growth factor α (TGFα) via receptor tyrosine kinases, c-fos/c-jun has been considered a point of intersection for cross-talk between the different signal transduction pathways. Recent evidence strongly implicates translocation of pro-TGFα into the nucleus as an important step preceding the initiation of hepatic DNA synthesis. We asked whether an active c-jun is required for the nuclear translocation of pro-TGFα and its stimulatory effect on DNA synthesis. For this purpose we used mice with c-jun inactivated post partum in hepatocytes by the Cre-loxP recombination system (c-junΔliver). Nuclear fractions from control and c-junΔliver mouse livers contained TGFα as pro-form of 17 kDa and the epidermal growth factor receptor (erbb-1) with molecular weights of 170 and 150 kDa (truncated form). Hepatocytes were isolated by collagenase perfusion and cultivated. A lack of c-jun did not alter the apoptotic activity but significantly suppressed DNA synthesis in the cultured hepatocytes. In control and c-junΔliver cells DNA synthesis was almost always associated with nuclear presence of pro-TGFα. 76.5 ± 6.8% of hepatocytes with pro-TGFα positive nuclei and only 4.52 ± 1.31% of hepatocytes with negative nuclei exhibited DNA replication. About 85% of the pro-TGFα positive nuclei also contained erbb-1. Treatment of cultures with mature TGFα or HGF elevated the frequency of pro-TGFα positive nuclei replicating DNA; HGF and TGFα-induced nuclear pro-TGFα and DNA synthesis significantly more in c-junΔliver than in control hepatocytes. These results suggest that (i) a lack of c-jun suppresses basal rates of DNA replication in hepatocytes; (ii) c-jun deficient hepatocytes show a pronounced growth response towards HGF or TGFα; (iii) nuclear translocation of pro-TGFα together with erbb-1 and its association with DNA synthesis are independent of c-jun.

Keywords: HGF, hepatocyte growth factor; LI, labelling index; PB, phenobarbital; pro-TGFα+, positive for pro-TGFα; pro-TGFα−, negative for pro-TGFα; TGFα, transforming growth factor α; TGF-β1, transforming growth factor β1

Journal Article.  5892 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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