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oai:repisalud.isciii.es:20.500.12105/110102024-11-29T21:24:24Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc 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 author 2020-05-13 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. Cancers (Basel) . 2020;12(5):1216 10.3390/cancers12051216 2072-6694 Cancers 32413989 http://hdl.handle.net/20.500.12105/11010 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.