2026-06-14T03:33:39Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/52172024-09-27T10:16:49Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19607

00925njm 22002777a 4500 dc Lopez-Mateo, Irene author Arruabarrena-Aristorena, Amaia author Artaza-Irigaray, Cristina author Lopez, Juan Antonio author Calvo, Enrique author Belandia, Borja author 2016 HEY1 (hairy/enhancer-of-split related with YRPW motif 1) is a member of the basic helix-loop-helix-orange (bHLH-O) family of transcription repressors that mediate Notch signalling. HEY1 acts as a positive regulator of the tumour suppressor p53 via still unknown mechanisms. A MALDI-TOF/TOF MS analysis has uncovered a novel HEY1 regulatory phosphorylation event at Ser-68. Strikingly, this single phosphorylation event controls HEY1 stability and function: simulation of HEY1 Ser-68 phosphorylation increases HEY1 protein stability but inhibits its ability to enhance p53 transcriptional activity. Unlike wild-type HEY1, expression of the phosphomimetic mutant HEY1-S68D failed to induce p53-dependent cell cycle arrest and it did not sensitize U2OS cells to p53-activating chemotherapeutic drugs. We have identified two related kinases, STK38 (serine/threonine kinase 38) and STK38L (serine/threonine kinase 38 like), which interact with and phosphorylate HEY1 at Ser-68. HEY1 is phosphorylated at Ser-68 during mitosis and it accumulates in the centrosomes of mitotic cells, suggesting a possible integration of HEY1-dependent signalling in centrosome function. Moreover, HEY1 interacts with a subset of p53-activating ribosomal proteins. Ribosomal stress causes HEY1 relocalization from the nucleoplasm to perinucleolar structures termed nucleolar caps. HEY1 interacts physically with at least one of the ribosomal proteins, RPL11, and both proteins cooperate in the inhibition of MDM2-mediated p53 degradation resulting in a synergistic positive effect on p53 transcriptional activity. HEY1 itself also interacts directly with MDM2 and it is subjected to MDM2-mediated degradation. Simulation of HEY1 Ser-68 phosphorylation prevents its interaction with p53, RPL11 and MDM2 and abolishes HEY1 migration to nucleolar caps upon ribosomal stress. Our findings uncover a novel mechanism for cross-talk between Notch signalling and nucleolar stress. Biosci Rep. 2016; 36(3):e00343 10.1042/BSR20160123 1573-4935 0144-8463 Bioscience reports 27129302 http://hdl.handle.net/20.500.12105/5217 centrosome HEY1 p53 phosphorylation ribosomal stress STK38 CYCLIN-DEPENDENT KINASE MITOTIC SPINDLE NUCLEOLAR CAPS P53 PROTEIN NOTCH PATHWAY CENTROSOMES CANCER HERP HEY1 functions are regulated by its phosphorylation at Ser-68