Carcinogenesis, Vol. 20, No. 4, 583-590,
April 1999
© 1999 Oxford University Press
HGF-mediated apoptosis via p53/bax-independent pathway activating JNK1
Laboratory of Experimental Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
Current studies have indicated both positive and negative roles for the hepatocyte growth factor (HGF)/c-met receptor signaling system in tumor development. Recently, we have shown that HGF has the capacity to induce both growth inhibition and programmed cell death in aflatoxin-transformed (AFLB8) rat liver epithelial cells. Using the same cell line, we have now investigated a potential mechanism for HGF-induced apoptosis. Immunoblot analysis of bcl-2 gene family member (bax, bcl-2, bclX-s/l) expression showed no correlation with HGF treatment, suggesting that HGF-mediated apoptosis is bax independent. Following HGF treatment retinoblastoma protein (pRB) was present in the hypophosphorylated state. HGF treatment increased cyclin A, cyclin G1 and nuclear transcriptional factor (NF
B) protein expression. However, electrophoretic mobility shift analysis showed that NFB activity decreased with HGF treatment. Under these apoptotic conditions, c-Jun N-terminal kinase (JNK1) and extracellular signal-regulated kinase (ERK2) were activated with lower level activation of ERK2, while no involvement of phosphatidylinositol-3 kinase was observed. Epidermal growth factor (EGF) was not protective, and actually induced cells to undergo apoptosis to a level similar to that of HGF alone or EGF/HGF in combination. These results suggest the possibility of cross-talk between HGF/c-met and EGF/EGFR signaling pathways, and the involvement of JNK1 induction in HGF-mediated apoptotic cell death.
Abbreviations: EGF, epidermal growth factor; ERKS, extracellular signal-regulated kinase; HGF, hepatocyte growth factor; ICE, interleukin-1-converting enzyme; IGF, insulin-like growth factor; INF
, interferon gamma; JNK, c-Jun N-terminal kinase; PBS, phosphate-buffered saline; PDGF, platelet-derived growth factor; PI3K, phosphatidylinositol-3 kinase; PTK, protein tyrosine kinase.
1 Present address: Semmelweis Medical University, I. Institute of Pathology, Üllói út 26, Budapest, Hungary
2 To whom correspondence should be addressed Email: snorri_thorgeirsson{at}nih.gov
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