2026-07-23T17:42:38Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/110102024-11-29T21:24:24Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597
Repisalud
author
Reglero, Clara
author
Rivas, Verónica
author
Albitre, Ángela
author
Ramos, Paula
author
Berciano, Susana R
author
Tapia, Olga
author
Martínez-Chantar, María L
author
Mayor, Federico
author
Penela, Petronila
author
Lafarga, Vanesa
funder
Instituto de Salud Carlos III
funder
Ministerio de Economía y Competitividad (España)
funder
Fundación Ramón Areces
funder
Comunidad de Madrid (España)
2020-09-14T10:34:17Z
2020-09-14T10:34:17Z
2020-05-13
Cancers (Basel) . 2020;12(5):1216
10.3390/cancers12051216
2072-6694
Cancers
32413989
http://hdl.handle.net/20.500.12105/11010
Adaptation to hypoxia is a common feature in solid tumors orchestrated by oxygen-dependent and independent upregulation of the hypoxia-inducible factor-1α (HIF-1α). We unveiled that G protein-coupled receptor kinase (GRK2), known to be overexpressed in certain tumors, fosters this hypoxic pathway via phosphorylation of the mRNA-binding protein HuR, a central HIF-1α modulator. GRK2-mediated HuR phosphorylation increases the total levels and cytoplasmic shuttling of HuR in response to hypoxia, and GRK2-phosphodefective HuR mutants show defective cytosolic accumulation and lower binding to HIF-1α mRNA in hypoxic Hela cells. Interestingly, enhanced GRK2 and HuR expression correlate in luminal breast cancer patients. GRK2 also promotes the HuR/HIF-1α axis and VEGF-C accumulation in normoxic MCF7 breast luminal cancer cells and is required for the induction of HuR/HIF1-α in response to adrenergic stress. Our results point to a relevant role of the GRK2/HuR/HIF-1α module in the adaptation of malignant cells to tumor microenvironment-related stresses.
eng
hypoxia
beta-adrenergic signaling
BREAST-CANCER CELLS
mRNA regulation
nucleocytoplasmic shuttling
GRK2
HuR
HIF1 alpha
VEGF
GRK2-Dependent HuR Phosphorylation Regulates HIF1α Activation under Hypoxia or Adrenergic Stress.
journal article
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GRK2-DependentHuRPhosphorylation_2020.pdf.txt
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