Acción biológica de la inmunofilina de alto peso molecular FKBP51 en procesos malignos
Immunophilins are a family of proteins with peptidylprolyl-isomerase activity that bind immunosuppressive drugs. FKBP51 is an Hsp90-binding cochaperone able to bind the macrolide FK506. In this study, it is demonstrated that FKBP51 is a phosphoprotein whose phosphorylation status affects its subcell...
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| Formato: | Tesis doctoral acceptedVersion |
| Lenguaje: | Español |
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Facultad de Farmacia y Bioquímica
2017
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| Acceso en línea: | http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=posgraafa&cl=CL1&d=HWA_2823 http://repositoriouba.sisbi.uba.ar/gsdl/collect/posgraafa/index/assoc/HWA_2823.dir/2823.PDF |
| Aporte de: |
| Sumario: | Immunophilins are a family of proteins with peptidylprolyl-isomerase activity that bind immunosuppressive drugs. FKBP51 is an Hsp90-binding cochaperone able to bind the macrolide FK506. In this study, it is demonstrated that FKBP51 is a phosphoprotein whose phosphorylation status affects its subcellular localization. This is regulated by the hormonal balance. An important fraction of FKBP51 is mitochondrial and translocates to the nucleus upon the onset of stress. Moreover, FKBP51 shows antiapoptotic properties and is overexpressed in cancer cells. The hTERT subunit of telomerase is also an Hsp90 client?protein highly expressed in cancer cells. FKBP51 co?immunoprecipitates with hTERT?HSP90 complexes. Both the Hsp90 inhibitor radicicol and the overexpression of the immunophilin TPR domain (required for such association) relocalizes hTERT to the cytoplasm. Importantly, telomerase activity is significantly enhanced by FKBP51. In vitro treatment of tumor cells with FK506 decreases cell viability, whereas in vivo treatment of Scid/Nod mice carrying xenographic tumors, significantly decreases tumor growth. Inasmuch as FK506 could also be bound by other immunophilins, SAFit2, a new selective compound for FKBP51 was assayed showing similar results. These studies demonstrate that FKBP51 is a novel antiapoptotic factor related to tumor development. |
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