Carcinogenesis Advance Access originally published online on March 28, 2003
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Carcinogenesis, Vol. 24, No. 5, 835-841,
May 2003
© 2003 Oxford University Press
CANCER BIOLOGY |
Induction of DNA synthesis in primary mouse hepatocytes is associated with nuclear pro-transforming growth factor 
and erbb-1 and is independent of c-jun
1 Institut für Krebsforschung, University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria
2 Research Institute of Molecular Pathology, Dr. Bohrgasse 7, A-1030 Vienna, Austria
3 To whom correspondence should be addressed Email: bettina.grasl-kraupp{at}univie.ac.at
For growth stimulation of liver cells by hepatocyte growth factor (HGF) or transforming growth factor 
(TGF) 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-TGF 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-TGF 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-jun
liver). Nuclear fractions from control and c-junliver mouse livers contained TGF 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-junliver cells DNA synthesis was almost always associated with nuclear presence of pro-TGF. 76.5 ± 6.8% of hepatocytes with pro-TGF positive nuclei and only 4.52 ± 1.31% of hepatocytes with negative nuclei exhibited DNA replication. About 85% of the pro-TGF positive nuclei also contained erbb-1. Treatment of cultures with mature TGF or HGF elevated the frequency of pro-TGF positive nuclei replicating DNA; HGF and TGF-induced nuclear pro-TGF and DNA synthesis significantly more in c-junliver 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 TGF; (iii) nuclear translocation of pro-TGF together with erbb-1 and its association with DNA synthesis are independent of c-jun.
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