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Campo DC | Valor | Lengua/Idioma |
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dc.contributor.author | Chowdhry, Sudhir | - |
dc.contributor.author | Zhang, Yiguo | - |
dc.contributor.author | McMahon, Michael | - |
dc.contributor.author | Sutherland, Calum | - |
dc.contributor.author | Cuadrado, Antonio | - |
dc.contributor.author | Hayes, John D. | - |
dc.date.accessioned | 2015-10-29T09:22:02Z | - |
dc.date.available | 2015-10-29T09:22:02Z | - |
dc.date.issued | 2013 | - |
dc.identifier | doi: 10.1038/onc.2012.388 | - |
dc.identifier | issn: 0950-9232 | - |
dc.identifier | e-issn: 1476-5594 | - |
dc.identifier.citation | Oncogene 32(32): 3765-3781 (2013) | - |
dc.identifier.uri | http://hdl.handle.net/10261/124069 | - |
dc.description | PMCID: PMC3522573 | - |
dc.description.abstract | Identification of regulatable mechanisms by which transcription factor NF-E2 p45-related factor 2 (Nrf2) is repressed will allow strategies to be designed that counter drug resistance associated with its upregulation in tumours that harbour somatic mutations in Kelch-like ECH-associated protein-1 (Keap1), a gene that encodes a joint adaptor and substrate receptor for the Cul3-Rbx1/Roc1 ubiquitin ligase. We now show that mouse Nrf2 contains two binding sites for β-transducin repeat-containing protein (β-TrCP), which acts as a substrate receptor for the Skp1-Cul1-Rbx1/Roc1 ubiquitin ligase complex. Deletion of either binding site in Nrf2 decreased β-TrCP-mediated ubiquitylation of the transcription factor. The ability of one of the two β-TrCP-binding sites to serve as a degron could be both increased and decreased by manipulation of glycogen synthase kinase-3 (GSK-3) activity. Biotinylated-peptide pull-down assays identified DSGIS 338 and DSAPGS 378 as the two β-TrCP-binding motifs in Nrf2. Significantly, our pull-down assays indicated that β-TrCP binds a phosphorylated version of DSGIS more tightly than its non-phosphorylated counterpart, whereas this was not the case for DSAPGS. These data suggest that DSGIS, but not DSAPGS, contains a functional GSK-3 phosphorylation site. Activation of GSK-3 in Keap1-null mouse embryonic fibroblasts (MEFs), or in human lung A549 cells that contain mutant Keap1, by inhibition of the phosphoinositide 3-kinase (PI3K)-protein kinase B (PKB)/Akt pathway markedly reduced endogenous Nrf2 protein and decreased to 10-50% of normal the levels of mRNA for prototypic Nrf2-regulated enzymes, including the glutamate-cysteine ligase catalytic and modifier subunits, glutathione S-transferases Alpha-1 and Mu-1, haem oxygenase-1 and NAD(P)H:quinone oxidoreductase-1. Pre-treatment of Keap1-/-MEFs or A549 cells with the LY294002 PI3K inhibitor or the MK-2206 PKB/Akt inhibitor increased their sensitivity to acrolein, chlorambucil and cisplatin between 1.9-fold and 3.1-fold, and this was substantially attenuated by simultaneous pre-treatment with the GSK-3 inhibitor CT99021. | - |
dc.description.sponsorship | We gratefully acknowledge Tenovus Scotland (T07/39), the Association for International Cancer Research (09-0254) and Cancer Research UK (C4909/A9990; C4909/A13786) for funding this work. | - |
dc.publisher | Nature Publishing Group | - |
dc.relation.isversionof | Postprint | - |
dc.rights | openAccess | - |
dc.title | Nrf2 is controlled by two distinct β-TrCP recognition motifs in its Neh6 domain, one of which can be modulated by GSK-3 activity | - |
dc.type | artículo | - |
dc.identifier.doi | 10.1038/onc.2012.388 | - |
dc.relation.publisherversion | http://dx.doi.org/10.1038/onc.2012.388 | - |
dc.date.updated | 2015-10-29T09:22:02Z | - |
dc.description.version | Peer Reviewed | - |
dc.language.rfc3066 | eng | - |
dc.contributor.funder | Cancer Research UK | - |
dc.contributor.funder | Tenovus Scotland | - |
dc.contributor.funder | Association for International Cancer Research | - |
dc.relation.csic | Sí | - |
dc.identifier.funder | http://dx.doi.org/10.13039/501100000289 | es_ES |
dc.identifier.funder | http://dx.doi.org/10.13039/100004435 | es_ES |
dc.identifier.pmid | 22964642 | - |
dc.type.coar | http://purl.org/coar/resource_type/c_6501 | es_ES |
item.fulltext | With Fulltext | - |
item.openairecristype | http://purl.org/coar/resource_type/c_18cf | - |
item.cerifentitytype | Publications | - |
item.grantfulltext | open | - |
item.openairetype | artículo | - |
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