1) La descarga del recurso depende de la página de origen
2) Para poder descargar el recurso, es necesario ser usuario registrado en Universia


Opción 1: Descargar recurso

Detalles del recurso

Descripción

Aims/hypothesis Rapamycin (sirolimus) is one of the primary immunosuppressants for islet transplantation. Yet there is evidence that the long-term treatment of islet-transplant patients with rapamycin may be responsible for subsequent loss of islet graft function and viability. Therefore, the primary objective of this study was to elucidate the molecular mechanism of rapamycin toxicity in beta cells. Methods Experiments were performed on isolated rat and human islets of Langerhans and MIN6 cells. The effects of rapamycin and the roles of mammalian target of rapamycin complex 2 (mTORC2)/protein kinase B (PKB) on beta cell signalling, function and viability were investigated using cell viability assays, insulin ELISA assays, kinase assays, western blotting, pharmacological inhibitors, small interfering (si)RNA and through the overproduction of a constitutively active mutant of PKB. Results Rapamycin treatment of MIN6 cells and islets of Langerhans resulted in a loss of cell function and viability. Although rapamycin acutely inhibited mTOR complex 1 (mTORC1), the toxic effects of rapamycin were more closely correlated to the dissociation and inactivation of mTORC2 and the inhibition of PKB. Indeed, the overproduction of constitutively active PKB protected islets from rapamycin toxicity whereas the inhibition of PKB led to a loss of cell viability. Moreover, the selective inactivation of mTORC2 using siRNA directed towards rapamycin-insensitive companion of target of rapamycin (RICTOR), mimicked the toxic effects of chronic rapamycin treatment. Conclusions/interpretation This report provides evidence that rapamycin toxicity is mediated by the inactivation of mTORC2 and the inhibition of PKB and thus reveals the molecular basis of rapamycin toxicity and the essential role of mTORC2 in maintaining beta cell function and survival.

Pertenece a

Faculty of Technology ePrints Service  

Autor(es)

Barlow, A. D. -  Xie, J. -  Moore, C. E. -  Campbell, S. C. -  Shaw, J. A. M. -  Nicholson, M. L. -  Herbert, T. P. - 

Id.: 70124912

Idioma: inglés  - 

Versión: 1.0

Estado: Final

Tipo:  application/pdf - 

Palabras claveB200 Pharmacology, Toxicology and Pharmacy - 

Tipo de recurso: Article  -  PeerReviewed  - 

Tipo de Interactividad: Expositivo

Nivel de Interactividad: muy bajo

Audiencia: Estudiante  -  Profesor  -  Autor  - 

Estructura: Atomic

Coste: no

Copyright: sí

: cc_by4

Formatos:  application/pdf - 

Requerimientos técnicos:  Browser: Any - 

Relación: [References] http://eprints.lincoln.ac.uk/28221/
[References] https://doi.org/10.1007/s00125-012-2475-7
[References] 10.1007/s00125-012-2475-7

Fecha de contribución: 07-oct-2017

Contacto:

Localización:
* Barlow, A. D. and Xie, J. and Moore, C. E. and Campbell, S. C. and Shaw, J. A. M. and Nicholson, M. L. and Herbert, T. P. (2012) Rapamycin toxicity in MIN6 cells and rat and human islets is mediated by the inhibition of mTOR complex 2 (mTORC2). Diabetologia, 55 (5). pp. 1355-1365. ISSN 0012-186X

Otros recursos de la mismacolección

  1. Pumping in oxygen Coverage of so called Islamic State (IS), as with the reporting of the jihadi threat in the “war aga...
  2. Traitors or toadies? [The BBC: myth of a public service, by Mills, Tom (Verso, pp266, £16.99)] From 1934 until 1984 that bastion of journalist integrity, the national treasure that is the BBC, ha...
  3. Time for a cover-up The most boring headline imaginable according, supposedly, to Claud Cockburn, is: “Small earthquake ...
  4. Animal and human emotion: concepts and methodologies The human-dog relationship is particularly interesting for the study of emotions. The underlying con...
  5. Indigenous self-determination: the root of state resistance States have long expressed some resistance towards granting the right of self-determination to ident...

Aviso de cookies: Usamos cookies propias y de terceros para mejorar nuestros servicios, para análisis estadístico y para mostrarle publicidad. Si continua navegando consideramos que acepta su uso en los términos establecidos en la Política de cookies.