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Authordc.contributor.authorCampos, Tania 
Authordc.contributor.authorZiehe, Javiera 
Authordc.contributor.authorFuentes Villalobos, Francisco 
Authordc.contributor.authorRiquelme, Orlando 
Authordc.contributor.authorPeña, Daniela 
Authordc.contributor.authorTroncoso Cotal, Rodrigo 
Authordc.contributor.authorLavandero González, Sergio
Authordc.contributor.authorMorín, Violeta 
Authordc.contributor.authorPincheira, Roxana 
Authordc.contributor.authorCastro, Ariel F. 
Cita de ítemdc.identifier.citationBiochimica et Biophysica Acta 1863 (2016) 1200–1207es_ES
Abstractdc.description.abstractTuberous sclerosis complex (TSC) disease results from inactivation of the TSC1 or TSC2 gene, and is characterized by benign tumors in several organs. Because TSC tumorigenesis correlates with hyperactivation of mTORC1, current therapies focus on mTORC1 inhibition with rapamycin or its analogs. Rapamycin-induced tumor shrinkage has been reported, but tumor recurrence occurs on withdrawal from rapamycin. Autophagy has been associated with development of TSC tumors and with tumor cell survival during rapamycin treatment mTORC1 and AMPK directly inhibit and activate autophagy, respectively. AMPK is hyperactivated in TSC cells and tumors, and drives cytoplasmic sequestration of the cell-cycle inhibitor p27KIP (p27). Whether AMPK and p27 are involved in rapamycin-induced autophagy and survival of TSC cells remain unexplored. Here, we show that inhibition of AMPK by compound C or by shRNA-mediated depletion of LKB1 reduces activation of autophagy by rapamycin in Tsc2-null cells. Similarly, shRNA-mediated depletion of p27 inhibited rapamycin-induced autophagy. In support of p27 lying downstream of AMPK on the activation of autophagy in Tsc2-null cells, a p27 mutant that preferentially localizes in the cytosol recovered the effect of rapamycin on autophagy in both p27- and LKB1-depleted cells, but a nuclear p27 mutant was inactive. Finally, we show that p27-dependent activation of autophagy is involved in Tsc2-null cell survival under rapamycin treatment. These results indicate that an AMPK/p27 axis is promoting a survival mechanism that could explain in part the relapse of TSC tumors treated with rapamycin, exposing new avenues for designing more efficient treatments for TSC patients.es_ES
Patrocinadordc.description.sponsorshipFONDECYT/CONICYT 1120923 1151031 FONDAP/CONICYT 15130011es_ES
Type of licensedc.rightsAttribution-NonCommercial-NoDerivs 3.0 Chile*
Link to Licensedc.rights.uri*
Sourcedc.sourceBiochimica et Biophysica Actaes_ES
Keywordsdc.subjectTuberous sclerosis complexes_ES
Keywordsdc.subjectCell survivales_ES
Títulodc.titleRapamycin requires AMPK activity and p27 expression for promoting autophagy-dependent Tsc2-null cell survivales_ES
Document typedc.typeArtículo de revistaes_ES
Indexationuchile.indexArtículo de publicación ISIes_ES

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Attribution-NonCommercial-NoDerivs 3.0 Chile
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivs 3.0 Chile