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Nat Biotechnol ; 20(5): 488-95, 2002 May.
Artigo em Inglês | MEDLINE | ID: mdl-11981563

RESUMO

Hepatocyte growth factor (HGF) and macrophage-stimulating protein (MSP) have an intrinsic dual nature: they are trophic cytokines preventing apoptosis on one side and scatter factors promoting invasion on the other. For therapeutic use, their anti-apoptotic activity must be separated from their pro-invasive activity. To this end, we engineered chimeric factors containing selected functional domains of HGF and/or MSP in different combinations, and tested their biological activity. Here we present a chimeric cytokine derived from the alpha-chains of HGF and MSP, named Metron factor 1 for its ability to concomitantly activate the HGF receptor (Met) and the MSP receptor (Ron). We provide evidence that Metron factor 1 prevents apoptosis and stimulates cell proliferation at nanomolar concentrations, but is devoid of any pro-invasive activity. In an in vivo murine model of drug-induced nephrotoxicity, intravenous injection of recombinant Metron factor 1 prevented renal damage and preserved tubular integrity.


Assuntos
Citocinas/metabolismo , Substâncias de Crescimento/metabolismo , Fator de Crescimento de Hepatócito/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Animais , Apoptose , Western Blotting , Divisão Celular , Linhagem Celular , Reagentes de Ligações Cruzadas/farmacologia , Dimerização , Relação Dose-Resposta a Droga , Células Epiteliais/patologia , Humanos , Rim/metabolismo , Ligantes , Camundongos , Modelos Biológicos , Ligação Proteica , Receptores de Fatores de Crescimento/metabolismo , Insuficiência Renal/metabolismo , Transdução de Sinais , Fatores de Tempo
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