Abstract
Basic fibroblast growth factor (bFGF) can exert mitogenic and viability-promoting effects in a wide range of biological systems. The biochemical activities mediating the cell survival function of bFGF are largely unknown. We report here that exposure of fibroblasts to bFGF, which confers upon them increased survival, also causes at the same time an increase in cellular levels of the Mdm2 oncoprotein. Cells constitutively exposed to a bFGF autocrine loop are more refractory to killing by cisplatin. This increased chemoresistance coincides with elevated Mdm2 and reduced activation of the endogenous p53, resulting in inefficient transcriptional activation of the bax gene promoter. Importantly, unlike Mdm2 accumulation in fibroblasts exposed to DNA damage, induction of Mdm2 by bFGF does not occur through a p53-mediated pathway. The role of p53 in DNA damage-induced apoptosis and the ability of Mdm2 to block p53-mediated cell death are well established. These findings therefore suggest that induction of Mdm2 and the subsequent inhibition of p53 function may contribute, at least partially, to the anti-apoptotic effects of bFGF and possibly some other survival factors.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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3T3 Cells / drug effects
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Animals
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Antineoplastic Agents
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Apoptosis / drug effects
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Apoptosis / genetics
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Cell Survival / drug effects
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Cell Survival / genetics
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Cisplatin / pharmacology
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Culture Media
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins / drug effects
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Cyclins / genetics
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DNA Damage / drug effects
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Fibroblast Growth Factor 2 / metabolism
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Fibroblast Growth Factor 2 / pharmacology*
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Gene Expression Regulation, Neoplastic
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Mice
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Nuclear Proteins*
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Promoter Regions, Genetic
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Proto-Oncogene Proteins / drug effects
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-bcl-2*
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Proto-Oncogene Proteins c-mdm2
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Rats
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
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bcl-2-Associated X Protein
Substances
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Antineoplastic Agents
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Bax protein, mouse
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Bax protein, rat
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Cdkn1a protein, mouse
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Cdkn1a protein, rat
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Culture Media
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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Nuclear Proteins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Tumor Suppressor Protein p53
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bcl-2-Associated X Protein
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Fibroblast Growth Factor 2
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Mdm2 protein, mouse
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Mdm2 protein, rat
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Proto-Oncogene Proteins c-mdm2
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Cisplatin