I graduated in Biochemistry at the University of Barcelona (1998), where I conducted my doctoral thesis (1999-2004). Since then, I have been studying the molecular mechanisms involved in physiological and pathological conditions, asking questions about basic research, participating in 20 projects. I have published twenty-one articles in international journals, all in the Q1, with nine as the first author and two as corresponding author. I have co-directed three doctoral theses and five bachelor’s theses. I have attended congresses and stablished collaborations (IRBLleida, UB, CBMSO). During the PhD, I completed a 3-month stay at the University of Cambridge (2003) and after that I moved to Universitat de Lleida (UdL, Juan de la Cierva contract, 2005-2009), the Molecular Biology Institute of Barcelona (IBMB, CSIC, 2010-2013) and returned to UdL in 2014. Since then, I have been teaching subjects related to Biochemistry as an associate professor.
EDUCATION
Biochemistry
Master in experimental Biochemistry (2000)
RESEARCH, TEACHING, or OTHER INTERESTS
General Biochemistry, Genetics and Molecular Biology, Cancer Research
22
Scopus Publications
Scopus Publications
Cytoplasmic cyclin D1 modulates brain cortex development Neus Pedraza, Daniel Rocandio, Bahira Zammou, Maria Ventura Monserrat, Ariadna Ortiz-Brugués, Pau Marfull-Oromí, Disha Chauhan, Mario Encinas, Xavier Dolcet, Francisco Ferrezuelo, Eloi Garí, Joaquim Egea Cellular and Molecular Life Sciences, 2026 During nervous system development, the interplay between cell cycle regulation and neurogenesis is fundamental to achieving the correct timing for neuronal differentiation. However, the molecules regulating this transition are poorly understood. Among these, the cell-cycle regulatory cyclins and their cyclin-dependent kinases (CDKs) play a pivotal role. In the present work we uncover an unknown function of cyclin D1 (CCND1) during cortex development which is independent of cell cycle regulation and that relies on its cytoplasmic localization and membrane association. We show that CCND1 is localized in the cytoplasm of the radial glial process (RGP) of neuron progenitors in different regions of the developing brain, including the pallium. Cytoplasmic CCND1 is enriched at the distal tip of the RGP, adjacent to the meningeal basement membrane, and overlaps with β1-integrin at the plasma membrane. Ccnd1 knock-out embryos show an abnormal cortical layering in which the distribution of TBR2 + and CTIP2 + cells are affected without displaying proliferation defects. This is consistent with a cytoplasmic function of CCND1 as overexpression by in utero electroporation of a dominant negative CCND1, unable to activate CDKs, and targeted to the cytoplasmic membranes, reproduces some of these TBR2 and CTIP2 defects. Finally, we provide evidence that cytoplasmic CCND1 affects neuron morphology and that it is required for the proper detachment of the RGP from the meningeal basement membrane by a mechanism involving the phosphorylation of the integrin effector protein paxillin. Hence, we propose that CCND1 has an important cytoplasmic function for cortical development independently of cell cycle regulation.
Crucial role of the NSE1 RING domain in Smc5/6 stability and FANCM-independent fork progression Neus P Lorite, Sonia Apostolova, Marta Guasch-Vallés, Aaron Pryer, Fernando Unzueta, Raimundo Freire, Roger Solé-Soler, Neus Pedraza, Xavier Dolcet, Eloi Garí, Neus Agell, Elaine M Taylor, Neus Colomina, Jordi Torres-Rosell Cellular and Molecular Life Sciences, 2024 The Smc5/6 complex is a highly conserved molecular machine involved in the maintenance of genome integrity. While its functions largely depend on restraining the fork remodeling activity of Mph1 in yeast, the presence of an analogous Smc5/6-FANCM regulation in humans remains unknown. We generated human cell lines harboring mutations in the NSE1 subunit of the Smc5/6 complex. Point mutations or truncations in the RING domain of NSE1 result in drastically reduced Smc5/6 protein levels, with differential contribution of the two zinc-coordinating centers in the RING. In addition, nse1-RING mutant cells display cell growth defects, reduced replication fork rates, and increased genomic instability. Notably, our findings uncover a synthetic sick interaction between Smc5/6 and FANCM and show that Smc5/6 controls fork progression and chromosome disjunction in a FANCM-independent manner. Overall, our study demonstrates that the NSE1 RING domain plays vital roles in Smc5/6 complex stability and fork progression through pathways that are not evolutionary conserved.
Cyclin D1—Cdk4 regulates neuronal activity through phosphorylation of GABAA receptors Neus Pedraza, Ma Ventura Monserrat, Francisco Ferrezuelo, Jordi Torres-Rosell, Neus Colomina, Federico Miguez-Cabello, Javier Picañol Párraga, David Soto, Esperanza López-Merino, Celia García-Vilela, José A. Esteban, Joaquim Egea, Eloi Garí Cellular and Molecular Life Sciences, 2023 Nuclear Cyclin D1 (Ccnd1) is a main regulator of cell cycle progression and cell proliferation. Interestingly, Ccnd1 moves to the cytoplasm at the onset of differentiation in neuronal precursors. However, cytoplasmic functions and targets of Ccnd1 in post-mitotic neurons are unknown. Here we identify the α4 subunit of gamma-aminobutyric acid (GABA) type A receptors (GABAARs) as an interactor and target of Ccnd1–Cdk4. Ccnd1 binds to an intracellular loop in α4 and, together with Cdk4, phosphorylates the α4 subunit at threonine 423 and serine 431. These modifications upregulate α4 surface levels, increasing the response of α4-containing GABAARs, measured in whole-cell patch-clamp recordings. In agreement with this role of Ccnd1–Cdk4 in neuronal signalling, inhibition of Cdk4 or expression of the non-phosphorylatable α4 decreases synaptic and extra-synaptic currents in the hippocampus of newborn rats. Moreover, according to α4 functions in synaptic pruning, CCND1 knockout mice display an altered pattern of dendritic spines that is rescued by the phosphomimetic α4. Overall, our findings molecularly link Ccnd1–Cdk4 to GABAARs activity in the central nervous system and highlight a novel role for this G1 cyclin in neuronal signalling.
Biomarkers Found in the Tumor Interstitial Fluid may Help Explain the Differential Behavior Among Keratinocyte Carcinomas Clara Matas-Nadal, Joan J. Bech-Serra, Sònia Gatius, Xavier Gomez, Marina Ribes-Santolaria, Marta Guasch-Vallés, Neus Pedraza, Josep M. Casanova, Carolina de la Torre Gómez, Eloi Garí, Rafael S. Aguayo-Ortiz Molecular and Cellular Proteomics, 2023 Basal cell carcinomas (BCCs) and cutaneous squamous cell carcinomas (SCCs) are the most frequent types of cancer, and both originate from the keratinocyte transformation, giving rise to the group of tumors called keratinocyte carcinomas (KCs). The invasive behavior is different in each group of KC and may be influenced by their tumor microenvironment. The principal aim of the study is to characterize the protein profile of the tumor interstitial fluid (TIF) of KC to evaluate changes in the microenvironment that could be associated with their different invasive and metastatic capabilities. We obtained TIF from 27 skin biopsies and conducted a label-free quantitative proteomic analysis comparing seven BCCs, 16 SCCs, and four normal skins. A total of 2945 proteins were identified, 511 of them quantified in more than half of the samples of each tumoral type. The proteomic analysis revealed differentially expressed TIF proteins that could explain the different metastatic behavior in both KCs. In detail, the SCC samples disclosed an enrichment of proteins related to cytoskeleton, such as Stratafin and Ladinin-1. Previous studies found their upregulation positively correlated with tumor progression. Furthermore, the TIF of SCC samples was enriched with the cytokines S100A8/S100A9. These cytokines influence the metastatic output in other tumors through the activation of NF-kB signaling. According to this, we observed a significant increase in nuclear NF-kB subunit p65 in SCCs but not in BCCs. In addition, the TIF of both tumors was enriched with proteins involved in the immune response, highlighting the relevance of this process in the composition of the tumor environment. Thus, the comparison of the TIF composition of both KCs provides the discovery of a new set of differential biomarkers. Among them, secreted cytokines such as S100A9 may help explain the higher aggressiveness of SCCs, while Cornulin is a specific biomarker for BCCs. Finally, the proteomic landscape of TIF provides key information on tumor growth and metastasis, which can contribute to the identification of clinically applicable biomarkers that may be used in the diagnosis of KC, as well as therapeutic targets.
Antitumor Effects of Ral-GTPases Downregulation in Glioblastoma Tània Cemeli, Marta Guasch-Vallés, Marina Ribes-Santolaria, Eva Ibars, Raúl Navaridas, Xavier Dolcet, Neus Pedraza, Neus Colomina, Jordi Torres-Rosell, Francisco Ferrezuelo, Judit Herreros, Eloi Garí International Journal of Molecular Sciences, 2022 Glioblastoma (GBM) is the most common tumor in the central nervous system in adults. This neoplasia shows a high capacity of growth and spreading to the surrounding brain tissue, hindering its complete surgical resection. Therefore, the finding of new antitumor therapies for GBM treatment is a priority. We have previously described that cyclin D1-CDK4 promotes GBM dissemination through the activation of the small GTPases RalA and RalB. In this paper, we show that RalB GTPase is upregulated in primary GBM cells. We found that the downregulation of Ral GTPases, mainly RalB, prevents the proliferation of primary GBM cells and triggers a senescence-like response. Moreover, downregulation of RalA and RalB reduces the viability of GBM cells growing as tumorspheres, suggesting a possible role of these GTPases in the survival of GBM stem cells. By using mouse subcutaneous xenografts, we have corroborated the role of RalB in GBM growth in vivo. Finally, we have observed that the knockdown of RalB also inhibits cell growth in temozolomide-resistant GBM cells. Overall, our work shows that GBM cells are especially sensitive to Ral-GTPase availability. Therefore, we propose that the inactivation of Ral-GTPases may be a reliable therapeutic approach to prevent GBM progression and recurrence.
Protective role of renal proximal tubular alpha-synuclein in the pathogenesis of kidney fibrosis Milica Bozic, Maite Caus, Raul R. Rodrigues-Diez, Neus Pedraza, Marta Ruiz-Ortega, Eloi Garí, Pilar Gallel, Maria José Panadés, Ana Martinez, Elvira Fernández, José Manuel Valdivielso Nature Communications, 2020 Kidney fibrosis is a highly deleterious process and a final manifestation of chronic kidney disease. Alpha-(α)-synuclein (SNCA) is an actin-binding neuronal protein with various functions within the brain; however, its role in other tissues is unknown. Here, we describe the expression of SNCA in renal epithelial cells and demonstrate its decrease in renal tubules of murine and human fibrotic kidneys, as well as its downregulation in renal proximal tubular epithelial cells (RPTECs) after TGF-β1 treatment. shRNA-mediated knockdown of SNCA in RPTECs results in de novo expression of vimentin and α-SMA, while SNCA overexpression represses TGF-β1-induced mesenchymal markers. Conditional gene silencing of SNCA in RPTECs leads to an exacerbated tubulointerstitial fibrosis (TIF) in two unrelated in vivo fibrotic models, which is associated with an increased activation of MAPK-p38 and PI3K-Akt pathways. Our study provides an evidence that disruption of SNCA signaling in RPTECs contributes to the pathogenesis of renal TIF by facilitating partial epithelial-to-mesenchymal transition and extracellular matrix accumulation.
Barley β-glucan accelerates wound healing by favoring migration versus proliferation of human dermal fibroblasts N.P. Fusté, M. Guasch, P. Guillen, C. Anerillas, T. Cemeli, N. Pedraza, F. Ferrezuelo, M. Encinas, M. Moralejo, E. Garí Carbohydrate Polymers, 2019 β-Glucans are considered candidates for the medication in different human pathologies. In this work, we have purified β-glucan from a selected barley line and tested their effects in primary human dermal fibroblasts. Unexpectedly, we have observed that this compound promoted a short-transitory proliferation arrest at 24 h after its addition on the medium. We have determined that this transitory arrest was dependent on the cell-cycle regulator protein Retinoblastoma. Moreover, dermal fibroblasts increase their migration capacities at 24 h after barley β-glucan addition. Also, we have described that barley β-glucan strongly reduced the ability of fibroblasts to attach and to spread on cell plates. Our data indicates that barley β-glucan signal induces an early response in HDF cells favoring migration versus proliferation. This feature is consistent with our observation that the topical addition of our barley β-glucan in vivo accelerates the wound closure in mouse skin.
Regulation of small GTPase activity by G1 cyclins Neus Pedraza, Tània Cemeli, Ma Ventura Monserrat, Eloi Garí, Francisco Ferrezuelo Small Gtpases, 2019 Together with a cyclin-dependent kinase (CDK) partner G1 cyclins control cell cycle entry by phosphorylating a number of nuclear targets and releasing a transcriptional program at the end of G1 phase. Yeast G1 cyclins also operate on cytoplasmic targets involved in the polarization of the cytoskeleton and vesicle trafficking. These processes are mainly controlled by the small GTPase Cdc42, and G1 cyclins regulate the activity of this and other small GTPases through the modulation of their regulators and effectors. This regulation is key for different developmental outcomes in unicellular organisms. In mammalian cells cytoplasmic G1 cyclin D1 has been shown to promote the activity of Rac1 and Ral GTPases and to block RhoA. Regulation of these small GTPases by G1 cyclins may constitute a mechanism to coordinate proliferation with cell migration and morphogenesis, important processes not only during normal development and organogenesis but also for tumor formation and metastasis. Here we briefly review the evidence supporting a role of G1 cyclins and CDKs as regulators of the activity of small GTPases, emphasizing their functional relevance both in budding yeast and in mammalian cells.
Recruitment of Staufen2 Enhances Dendritic Localization of an Intron-Containing CaMKIIα mRNA Raúl Ortiz, Maya V. Georgieva, Sara Gutiérrez, Neus Pedraza, Sandra M. Fernández-Moya, Carme Gallego Cell Reports, 2017 Regulation of mRNA localization is a conserved cellular process observed in many types of cells and organisms. Asymmetrical mRNA distribution plays a particularly important role in the nervous system, where local translation of localized mRNA represents a key mechanism in synaptic plasticity. CaMKIIα is a very abundant mRNA detected in neurites, consistent with its crucial role at glutamatergic synapses. Here, we report the presence of CaMKIIα mRNA isoforms that contain intron i16 in dendrites, RNA granules, and synaptoneurosomes from primary neurons and brain. This subpopulation of unspliced mRNA preferentially localizes to distal dendrites in a synaptic-activity-dependent manner. Staufen2, a well-established marker of RNA transport in dendrites, interacts with intron i16 sequences and enhances its distal dendritic localization, pointing to the existence of intron-mediated mechanisms in the molecular pathways that modulate dendritic transport and localization of synaptic mRNAs.
Characterization of cytoplasmic cyclin D1 as a marker of invasiveness in cancer Noel P. Fusté, Esmeralda Castelblanco, Isidre Felip, Maria Santacana, Rita Fernández-Hernández, Sònia Gatius, Neus Pedraza, Judit Pallarés, Tània Cemeli, Joan Valls, Marc Tarres, Francisco Ferrezuelo, Xavier Dolcet, Xavier Matias-Guiu, Eloi Garí Oncotarget, 2016
