Biology subjects

de la Luna, S.

Publications and source records attributed to de la Luna, S..

5 recordsLinked to original sources

bioRxiv2025

DYRK1A regulates cancer cell and cancer-associated fibroblast secretomes to foster an immunosuppressive microenvironment in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a desmoplastic, immunosuppressive stroma dominated by cancer-associated fibroblasts (CAFs). Paracrine signals from cancer cells and CAFs shape the tumor microenvironment (TME), facilitating interactions that drive tumor growth and immune evasion, yet the molecular regulators of this crosstalk remain incompletely understood. Here, we show that Dual-specificity Tyrosine-Regulated Kinase 1A (DYRK1A), previously shown to promote PDAC growth by stabilizing c-MET in cancer cells, is also expressed in CAFs at levels comparable to those in cancer cells. Secretome profiling of DYRK1A-depleted cancer cells and CAFs by quantitative mass spectrometry revealed DYRK1A-dependent factors in each cell type associated with terms related to cell migration, while combining the DYRK1A-regulated proteins from both compartments highlighted additional categories associated with immune infiltration and cell-cell interactions in the TME. Genetic or pharmacological inhibition of DYRK1A reduced CCL2, CCL5 and CSF-1 secretion in cancer cells, and CXCL12 in CAFs, linking DYRK1A activity to immunosuppressive paracrine signaling. Conditioned media from DYRK1A-depleted cancer cells or CAFs impaired the migration of monocytes and myeloid-derived suppressor cells, indicating that DYRK1A remodels the PDAC secretome to recruit immunosuppressive myeloid populations. These findings extend the established role of DYRK1A beyond cancer cell-intrinsic signaling, highlighting its role as a regulator of secreted factors that shape the PDAC TME, and position this kinase as a potential target to reduce immunosuppressive signaling. SignificanceDYRK1A regulates chemokine and cytokine secretion in PDAC cancer cells and CAFs, promoting recruitment of immunosuppressive myeloid populations, and revealing a previously unrecognized role for this kinase in shaping the TME.

cancer biology↗

bioRxiv2024

THE DUAL-SPECIFICITY KINASE DYRK1A INTERACTS WITH THE HEPATITIS B VIRUS GENOME AND REGULATES THE PRODUCTION OF VIRAL RNA

The genome of Hepatitis B virus (HBV) persists in infected hepatocytes as a nuclear episome (cccDNA) that is responsible for the transcription of viral genes and viral rebound, following antiviral treatment arrest in chronically infected patients. Beside pegylated interferon-alpha, there is currently no clinically approved therapeutic protocol able to target cccDNA [1]. The development of alternative strategies aiming at permanently abrogating HBV RNA production requires a thorough understanding of cccDNA transcriptional and post-transcriptional regulation. In a previous study, we discovered that 1C8, a compound that inhibits the phosphorylation of some cellular RNA-binding proteins (RBPs), could decrease the level of HBV RNAs. Here, we aimed at identifying kinases responsible for this effect. Among the kinases targeted by 1C8, we focused on DYRK1A, a dual-specificity kinase that controls the transcription of cellular genes by phosphorylating transcription factors, histones, chromatin regulators as well as RNA polymerase II. The results of a combination of genetic and chemical approaches using HBV-infected hepatocytes, indicated that DYRK1A positively regulates the production of HBV RNAs. In addition, we found that DYRK1A associates with cccDNA, and stimulates the production of HBV nascent RNAs. Finally, reporter gene assays showed that DYRK1A up-regulates the activity of the HBV enhancer 1/X promoter in a sequence-dependent manner. Altogether, these results indicate that DYRK1A is a proviral factor that may participate in the the HBV life cycle by stimulating the production of HBx, a viral factor absolutely required to trigger the complete cccDNA transcriptional program.

microbiology↗

bioRxiv2021

The DYRK1A protein kinase regulates ribosome mass and translation rates through transcriptional control of ribosomal protein genes expression

Ribosomal proteins (RPs) are evolutionary conserved proteins that are essential for protein translation. RP expression must be tightly regulated to ensure the appropriate assembly of ribosomes and to respond to the growth demands of cells. The elements regulating the transcription of RP genes (RPGs) have been characterized in yeast and Drosophila, yet how cells regulate the production of RPs in mammals is less well understood. Here, we show that a subset of RPG promoters is characterized by the presence of the palindromic TCTCGCGAGA motif and marked by the recruitment of the protein kinase DYRK1A. The presence of DYRK1A at these promoters is associated with enhanced binding of the TATA-binding protein, TBP, and it is negatively correlated with the binding of the GABP transcription factor, establishing at least two clusters of RPGs that could be coordinately regulated. However, DYRK1A silencing leads to a global reduction of RPGs, mRNA pointing at DYRK1A activities beyond those dependent on its chromatin association. Significantly, cells in which DYRK1A is depleted have reduced RP levels, fewer ribosomes, reduced global protein synthesis and smaller size. We therefore propose a novel role for DYRK1A in coordinating the expression of genes encoding RPs, thereby controlling cell growth in mammals.

molecular biology↗

bioRxiv2018

TFIIIC dynamically binds Alu elements to control gene expression through chromatin looping

Folding of the mammalian genome is governed by architectural proteins, such as CTCF. TFIIIC, a RNA polymerase III transcription factor, has been identified as an insulator but its role in genome topology is totally unknown. Here, we show that TFIIIC establishes long-range genomic interactions that affect gene expression. Upon serum starvation (SS), TFIIIC occupancy increases at Alu elements (AEs) near promoters of cell cycle-related genes. Bound AEs become H3K18 hyper-acetylated and fold to contact distal pre-loaded CTCF sites near other cell cycle genes. The promoters of these genes also become hyper-acetylated ensuring their basal transcription during SS and their increased expression during serum re-exposure. Ablation of TFIIIC or deletion of the TFIIIC-bound AE that loops to the G2/M cycling F (CCNF) locus affects its expression and nuclear positioning. These results illustrate a novel function of human TFIIIC in changing 3D genome topology through the epigenetic state of AEs.\n\nHighlightsO_LISerum starvation enhances TFIIIC binding to Alu Elements (AEs) near cell cycle genes\nC_LIO_LIBinding of TFIIIC increases H3K18 acetylation over the bound AE\nC_LIO_LITFIIIC-mediated looping to distal genes favors their reactivation upon serum addition\nC_LIO_LILong-range TFIIIC interactions tune cell cycle genes expression through nuclear repositioning\nC_LI\n\nGraphical abstract\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=64 SRC=\"FIGDIR/small/455733_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (22K):\norg.highwire.dtl.DTLVardef@917ee4org.highwire.dtl.DTLVardef@21d0fborg.highwire.dtl.DTLVardef@1f1a17org.highwire.dtl.DTLVardef@1e9df24_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2018

Impaired development of neocortical circuits contributes to the neurological alterations in DYRK1A haploinsufficiency syndrome

Autism spectrum disorders are early onset neurodevelopmental disorders characterized by deficits in social communication and restricted repetitive behaviors, yet they are quite heterogeneous in terms of their genetic basis and phenotypic manifestations. Recently, de novo pathogenic mutations in DYRK1A, a chromosome 21 gene associated to neuropathological traits of Down syndrome, have been identified in patients presenting a recognizable syndrome included in the autism spectrum. These mutations produce DYRK1A kinases with partial or complete absence of the catalytic domain, or they represent missense mutations located within this domain. Here, we undertook an extensive biochemical characterization of the DYRK1A missense mutations reported to date and show that most of them, but not all, result in enzymatically dead DYRK1A proteins. We also show that haploinsufficient Dyrk1a+/- mutant mice mirror the neurological traits associated with the human pathology, such as defective social interactions, stereotypic behaviors and epileptic activity. These mutant mice present altered proportions of excitatory and inhibitory neocortical neurons and synapses. Moreover, we provide evidence that alterations in the production of cortical excitatory neurons are contributing to these defects. Indeed, by the end of the neurogenic period, the expression of developmental regulated genes involved in neuron differentiation and/or activity is altered. Therefore, our data indicate that altered neocortical neurogenesis could critically affect the formation of cortical circuits, thereby contributing to the neuropathological changes in DYRK1A haploinsufficiency syndrome.

neuroscience↗