A5019380304- Protein Degradation and Inhibitors
- Cancer-related gene regulation
- Histone Deacetylase Inhibitors Research
- PI3K/AKT/mTOR signaling in cancer
- Cancer-related Molecular Pathways
- Lymphoma Diagnosis and Treatment
- Epigenetics and DNA Methylation
- Cancer Research and Treatments
- 14-3-3 protein interactions
- Immune Cell Function and Interaction
- Telomeres, Telomerase, and Senescence
- Cancer, Hypoxia, and Metabolism
- T-cell and B-cell Immunology
- DNA Repair Mechanisms
- Mitochondrial Function and Pathology
- Genomics, phytochemicals, and oxidative stress
- Genetics, Aging, and Longevity in Model Organisms
- Advanced Breast Cancer Therapies
- Ubiquitin and proteasome pathways
- Adipose Tissue and Metabolism
- Muscle Physiology and Disorders
- Pluripotent Stem Cells Research
- RNA regulation and disease
- Nuclear Receptors and Signaling
- Renal and related cancers
Spanish National Cancer Research Centre
2011-2024
Centro de Biología Molecular Severo Ochoa
2023-2024
Centro de Investigación del Cáncer
2007-2023
Memorial Sloan Kettering Cancer Center
2014-2020
Kettering University
2015
Abstract Somatic mutations in CREBBP occur frequently B-cell lymphoma. Here, we show that loss of facilitates the development germinal center (GC)–derived lymphomas mice. In both human and murine lymphomas, loss-of-function resulted focal depletion enhancer H3K27 acetylation aberrant transcriptional silencing genes regulate signaling immune responses, including class II MHC. Mechanistically, CREBBP-regulated enhancers are counter-regulated by BCL6 repressor a complex with SMRT HDAC3, which...
A recent study conducted in mice reported that liver-specific knockout of tumor suppressor Pten augments nuclear factor (erythroid-derived 2)-like 2 (NRF2) transcriptional activity. Here, we further investigated how phosphatase and tensin homolog deleted on chromosome 10 (PTEN) controls NRF2 the relevance this pathway human carcin ogenesis.Drug genetic targeting to PTEN phosphoproteomics approaches indicated leads glycogen synthase kinase-3 (GSK-3)-mediated phosphorylation at residues...
Abstract The mechanistic target of rapamycin complex 1 controls cellular anabolism in response to growth factor signaling and nutrient sufficiency signaled through the Rag GTPases. Inhibition mTOR reproducibly extends longevity across eukaryotes. Here we report that mice endogenously express active mutant variants RagC exhibit multiple features parenchymal damage include senescence, expression inflammatory molecules, increased myeloid inflammation with extensive inflammaging a ~30% reduction...
Abstract Cellular senescence is emerging as an important in vivo anticancer response elicited by multiple stresses, including currently used chemotherapeutic drugs. Nutlin-3a a recently discovered small-molecule antagonist of the p53-destabilizing protein murine double minute-2 (MDM2) that induces cell cycle arrest and apoptosis cancer cells with functional p53. Here, we report nutlin-3a cellular primary fibroblasts, oncogenically transformed fibrosarcoma lines. No evidence drug-induced was...
The crucial function of the PTEN tumor suppressor in multiple cellular processes suggests that its activity must be tightly controlled. Both, membrane association and a variety post-translational modifications, such as acetylation, phosphorylation, mono- polyubiquitination, have been reported to regulate activity. Here, we demonstrated is also post-translationally modified by small ubiquitin-like proteins, ubiquitin-related modifier 1 (SUMO1) SUMO2. We identified lysine residue 266 major...
Recent studies in human fibroblasts have provided a new general paradigm of tumor suppression according to which oncogenic signaling produces DNA damage and this, turn, results ATM/p53-dependent cellular senescence. Here, we tested this model variety murine experimental systems. Overexpression Ras efficiently induced senescence but occurred the absence detectable signaling, thus suggesting fundamental difference between cells. Moreover, lung adenomas initiated by endogenous levels K-Ras...
The mechanistic target of rapamycin complex 1 (mTORC1) integrates cellular nutrient signaling and hormonal cues to control metabolism. We have previously shown that constitutive mTORC1 by means genetic activation RagA (expression GTP-locked RagA, or RagAGTP) in mice resulted a fatal energetic crisis at birth. Herein, we rescue neonatal lethality RagAGTP find morphometric metabolic alterations span glucose, lipid, ketone, bile acid amino homeostasis adults, median lifespan nine months....
Ionizing radiation induces DNA Double-Strand Breaks (DSBs) which activate the ATM/CHEK2/p53 pathway leading to cell cycle arrest and apoptosis through transcription of genes including CDKN1A (p21) BBC3 (PUMA). This prevents genomic instability tumorigenesis as demonstrated in heritable syndromes [e.g. Ataxia Telangiectasia (AT); Li-Fraumeni syndrome (LFS)]. Here, a simple assay based on gene expression peripheral blood measure accurately activity is described. The p21, Puma Sesn2 was...
Nerve growth factor receptor (NGFR) is expressed by follicular dendritic cells (FDCs). However, the role of NGFR in humoral response not well defined. Here, we study effect Ngfr loss on lymph node organization and function, demonstrating that depletion leads to spontaneous germinal center (GC) formation an expansion GC B cell compartment. In accordance with this effect, stromal are altered
The long-term risk of malignancy associated with stem cell therapies is a significant concern in the clinical application this exciting technology. We report cancer-selective strategy to enhance safety therapies. Briefly, using engineering approach, we show that aggressive cancers derived from human or murine induced pluripotent cells (iPSCs) and embryonic (ESCs) are strikingly sensitive temporary MYC blockade. On other hand, differentiated tissues mouse iPSCs can readily tolerate...
B lymphocytes are exquisitely sensitive to fluctuations in nutrient signaling by the Rag GTPases, and 15% of follicular lymphomas (FLs) harbor activating mutations RRAGC. Hence, a potential therapeutic approach against malignant cells is inhibit GTPase signaling, but because such inhibitors still be developed, efficacy safety remain unknown. We generated knockin mice expressing hypomorphic variant RagC (Q119L); RagCQ119L/+ viable show attenuated signaling. lymphocyte activation...
Abstract The expression of the Nerve growth factor receptor (NGFR) has been described in follicular dendritic cells (FDCs), major lymphoid stromal cell (LSC) compartment regulating B-cell activation within germinal centers (GCs). However, role NGFR humoral response is not well defined. In this work, we have studied effect Ngfr KO LNs organization and function. led to spontaneous GC formation expansion which were related depletion non-hematopoietic radioresistant compartment. agreement, mice...
Abstract Follicular lymphoma (FL) is a common and incurable form indolent B-cell lymphoma. Genomic studies have now catalogued many recurrent mutations in FL. Epigenetic regulators emerged as the most targets of somatic point mutations. For example, histone methyltransferase KMT2D (MLL4/MLL2) frequently mutated gene FL with reported mutational frequencies up to 84%. However, transcriptional biological consequences loss function are currently unknown. Using well-described murine model FL, we...
Abstract Genomic studies have revealed surprising new insights into the genetics of human B-cell lymphomas. Of particular note lysine-specific methyl transferase KMT2D has emerged as one most frequently mutated genes in follicular lymphoma (FL) and diffuse large (DLBCL). However, biological consequences mutations are not known. Here we show that functions a bona fide tumor suppressor promotes development vivo. Integrative analyses function indicate specific focal effects on H3K4 methylation...
Abstract Follicular lymphoma (FL), a form of non-Hodgkin lymphoma, is the second most common B-cell and remains incurable in majority cases despite recent advances therapy. Following an indolent phase, 50% patients suffer disease transformation to aggressive (transformed FL; tFL). This dramatic switch behavior typically culminates rapid deterioration patient demise. Accordingly, much effort has been focused on understanding genetics resulted identification key genetic lesions (e.g. MYC...
Supplementary Figure 1 from Induction of p53-Dependent Senescence by the MDM2 Antagonist Nutlin-3a in Mouse Cells Fibroblast Origin