2026-06-14T03:44:09Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/51602024-09-27T10:09:18Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19607
Repisalud
author
Hill, Richard
author
Madureira, Patricia A.
author
Ferreira, Bibiana
author
Baptista, Ines
author
Machado, Susana
author
Colaco, Laura
author
dos Santos, Marta
author
Liu, Ningshu
author
Dopazo, Ana
author
Ugurel, Selma
author
Adrienn, Angyal
author
Kiss-Toth, Endre
author
Isbilen, Murat
author
Gure, Ali O.
author
Link, Wolfgang
funder
Bayer Healthcare Pharmaceuticals-Bayer Pharma AG
funder
Fundação para a Ciência e Tecnologia (Portugal)
2017-10-20T10:33:49Z
2017-10-20T10:33:49Z
2017
Nat Commun. 2017; 8:14687
10.1038/ncomms14687
2041-1723
Nature Communications
28276427
http://hdl.handle.net/20.500.12105/5160
Intrinsic and acquired resistance to chemotherapy is the fundamental reason for treatment failure for many cancer patients. The identification of molecular mechanisms involved in drug resistance or sensitization is imperative. Here we report that tribbles homologue 2 (TRIB2) ablates forkhead box O activation and disrupts the p53/MDM2 regulatory axis, conferring resistance to various chemotherapeutics. TRIB2 suppression is exerted via direct interaction with AKT a key signalling protein in cell proliferation, survival and metabolism pathways. Ectopic or intrinsic high expression of TRIB2 induces drug resistance by promoting phospho-AKT (at Ser473) via its COP1 domain. TRIB2 expression is significantly increased in tumour tissues from patients correlating with an increased phosphorylation of AKT, FOXO3a, MDM2 and an impaired therapeutic response. This culminates in an extremely poor clinical outcome. Our study reveals a novel regulatory mechanism underlying drug resistance and suggests that TRIB2 functions as a regulatory component of the PI3K network, activating AKT in cancer cells.
eng
SIGNAL-TRANSDUCTION
MELANOMA
PATHWAY
CELLS
PHENOTYPE
SURVIVAL
AKT/PKB
MDM2
FOXO
P53
TRIB2 confers resistance to anti-cancer therapy by activating the serine/threonine protein kinase AKT
journal article
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https://repisalud.isciii.es/bitstreams/baf12acd-1b9b-481e-abb1-56c3e4b933b4/download
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TRIB2ConfersResistanceTo_2017
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f15ab0d4bc5c0f06f9f87ba023210b4c
51005
text/plain
TRIB2ConfersResistanceTo_2017.txt