Person: Molina Martín, María
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First Name
María
Last Name
Molina Martín
Affiliation
Universidad Complutense de Madrid
Faculty / Institute
Farmacia
Department
Microbiología y Parasitología
Area
Microbiología
Identifiers
6 results
Search Results
Now showing 1 - 6 of 6
Item A global analysis of the reconstitution of PTEN function by translational readthrough of PTEN pathogenic premature termination codons(Human mutation, 2021) Luna, Sandra; Torices, Leire; Mingo, Janire; Amo, Laura; Ruiz‐Ibarlucea, Pablo; Erramuzpe, Asier; Cortés, Jesús M.; Tejada, María I.; Nunes‐Xavier, Caroline E.; López, José I.; Pulido, Rafael; Rodríguez Escudero, María Isabel; Jiménez Cid, Víctor; Molina Martín, MaríaThe PTEN tumor suppressor gene is mutated with high incidence in tumors and in thegermline of patients with cancer predisposition or with macrocephaly associatedwith autism.PTENnonsense mutations generating premature termination codons (PTC)and producing nonfunctional truncated PTEN proteins are frequent in association withhuman disease. However, there are no studies addressing the restoration of full‐lengthPTEN proteins from the PTC‐mutatedPTENgene by translational readthrough. Here,we have performed a global translational and functional readthrough analysis of thecomplete collection ofPTENPTC somatic or hereditary mutations found in tumors or inthegermlineofpatients(disease‐associated PTEN PTCome), and we set standards forthe analysis of the potential of readthrough functional reconstitution in disease‐relevant genes. Our analysis indicates that prevalent pathogenicPTENPTC mutationsare susceptible to PTEN functional restoration in response to readthrough‐inducingcompounds. Comprehensive readthrough analyses of disease‐associated PTComes willbe valuable tools for the implementation of readthrough‐based precision interventionsin specific groups of patientsItem Clotrimazole-Induced Oxidative Stress Triggers Novel Yeast Pkc1-Independent Cell Wall Integrity MAPK Pathway Circuitry(Journal of Fungi, 2021) Sellers Moya, Ángela; Nuévalos, Marcos; Molina Martín, María; Martín Brieva, HumbertoAzoles are one of the most widely used drugs to treat fungal infections. To further understand the fungal response to azoles, we analyzed the MAPK circuitry of the model yeast Saccharomyces cerevisiae that operates under treatment with these antifungals. Imidazoles, and particularly clotrimazole, trigger deeper changes in MAPK phosphorylation than triazoles, involving a reduction in signaling through the mating pathway and the activation of the MAPKs Hog1 and Slt2 from the High-Osmolarity Glycerol (HOG) and the Cell Wall Integrity (CWI) pathways, respectively. Clotrimazole treatment leads to actin aggregation, mitochondrial alteration, and oxidative stress, which is essential not only for the activation of both MAPKs, but also for the appearance of a low-mobility form of Slt2 caused by additional phosphorylation to that occurring at the conserved TEY activation motif. Clotrimazole-induced ROS production and Slt2 phosphorylation are linked to Tpk3-mediated PKA activity. Resistance to clotrimazole depends on HOG and CWI-pathway-mediated stress responses. However, Pkc1 and other proteins acting upstream in the pathway are not critical for the activation of the Slt2 MAPK module, suggesting a novel rewiring of signaling through the CWI pathway. We further show that the strong impact of azole treatment on MAPK signaling is conserved in other yeast species.Item A trans-kingdom T6SS effector induces the fragmentation of the mitochondrial network and activates innate immune receptor NLRX1 to promote infection(Nat. Commun., 2023) Sá-Pessoa, Joana; López-Montesino, Sara; Przybyszewska, Kornelia; Marshall, Helina; Ova, Adelia; Schroeder, Gunnar N; Barabas, Peter; Curtis, Tim; Bengoechea, Jose A; Rodríguez Escudero, María Isabel; Jiménez Cid, Víctor; Molina Martín, MaríaBacteria can inhibit the growth of other bacteria by injecting effectors using a type VI secretion system (T6SS). T6SS effectors can also be injected into eukaryotic cells to facilitate bacterial survival, often by targeting the cytoskeleton. Here, we show that the trans-kingdom antimicrobial T6SS effector VgrG4 from Klebsiella pneumoniae triggers the fragmentation of the mitochondrial network. VgrG4 colocalizes with the endoplasmic reticulum (ER) protein mitofusin 2. VgrG4 induces the transfer of Ca2+ from the ER to the mitochondria, activating Drp1 (a regulator of mitochondrial fission) thus leading to mitochondrial network fragmentation. Ca2+ elevation also induces the activation of the innate immunity receptor NLRX1 to produce reactive oxygen species (ROS). NLRX1-induced ROS limits NF-κB activation by modulating the degradation of the NF-κB inhibitor IκBα. The degradation of IκBα is triggered by the ubiquitin ligase SCFβ-TrCP, which requires the modification of the cullin-1 subunit by NEDD8. VgrG4 abrogates the NEDDylation of cullin-1 by inactivation of Ubc12, the NEDD8-conjugating enzyme. Our work provides an example of T6SS manipulation of eukaryotic cells via alteration of the mitochondria.Item Educating in antimicrobial resistance awareness: adaptation of the Small World Initiative program to service-learning.(FEMS Microbiology Letters, 2018) Valderrama, María José; González Zorn, Bruno; Calvo de Pablo, Pilar; Díez Orejas, Rosalía María; Fernández Acero, Teresa; Gil Serna, Jessica; Juan Ferré, Lucía De; Martín Brieva, Humberto; Molina Martín, María; Navarro García, Federico; Patiño, Belén; Pla Alonso, Jesús; Prieto, Daniel; Rodríguez Fernández, Carmina; Román González, Elvira; Sanz Santamaría, Ana Belén; Silóniz, María Isabel de; Suárez Rodríguez, Mónica; Vázquez, Covadonga; Jiménez Cid, VíctorThe Small World Initiative (SWI) and Tiny Earth are a consolidated and successful education programs rooted in the USA that tackle the antibiotic crisis by a crowdsourcing strategy. Based on active learning, it challenges young students to discover novel bioactive-producing microorganisms from environmental soil samples. Besides its pedagogical efficiency to impart microbiology content in academic curricula, SWI promotes vocations in research and development in Experimental Sciences and, at the same time, disseminates the antibiotic awareness guidelines of the World Health Organization. We have adapted the SWI program to the Spanish academic environment by a pioneering hierarchic strategy based on service-learning that involves two education levels (higher education and high school) with different degrees of responsibility. Throughout the academic year, 23 SWI teams, each consisting of 3-7 undergraduate students led by one faculty member, coordinated off-campus programs in 22 local high schools, involving 597 high school students as researchers. Post-survey-based evaluation of the program reveals a satisfactory achievement of goals: acquiring scientific abilities and general or personal competences by university students, as well as promoting academic decisions to inspire vocations for science- and technology-oriented degrees in younger students, and successfully communicating scientific culture in antimicrobial resistance to a young stratum of society.Item Mitogen-Activated Protein Kinase Phosphatases (MKPs) in Fungal Signaling: Conservation, Function, and Regulation.(International journal of molecular sciences, 2019) González Rubio, Gema; Fernández Acero, Teresa; Martín, Humberto; Molina Martín, MaríaMitogen-activated protein kinases (MAPKs) are key mediators of signaling in fungi, participating in the response to diverse stresses and in developmental processes. Since the precise regulation of MAPKs is fundamental for cell physiology, fungi bear dual specificity phosphatases (DUSPs) that act as MAP kinase phosphatases (MKPs). Whereas fungal MKPs share characteristic domains of this phosphatase subfamily, they also have specific interaction motifs and particular activation mechanisms, which, for example, allow some yeast MKPs, such as Sdp1, to couple oxidative stress with substrate recognition. Model yeasts show that MKPs play a key role in the modulation of MAPK signaling flow. Mutants affected in Msg5 or in Pmp1 display MAPK hyperactivation and specific phenotypes. MKPs from virulent fungi, such as Cpp1, Msg5, and Pmp1, are relevant for pathogenicity. Apart from transcriptional regulation, MKPs can be post-transcriptionally regulated by RNA-binding proteins such as Rnc1, which stabilizes the mRNA. Pmp1 activity and Msg5 stability are regulated by phosphorylation and ubiquitination, respectively. Therefore, fungi offer a platform to gain insight into the regulatory mechanisms that control MKPs.Item A functional dissection of PTEN N-terminus: implications in PTEN subcellular targeting and tumor suppressor activity.(PloS one, 2015) Gil, Anabel; Rodríguez Escudero, María Isabel; Stumpf, Miriam; Molina Martín, María; Jiménez Cid, Víctor; Pulido, RafaelSpatial regulation of the tumor suppressor PTEN is exerted through alternative plasma membrane, cytoplasmic, and nuclear subcellular locations. The N-terminal region of PTEN is important for the control of PTEN subcellular localization and function. It contains both an active nuclear localization signal (NLS) and an overlapping PIP2-binding motif (PBM) involved in plasma membrane targeting. We report a comprehensive mutational and functional analysis of the PTEN N-terminus, including a panel of tumor-related mutations at this region. Nuclear/cytoplasmic partitioning in mammalian cells and PIP3 phosphatase assays in reconstituted S. cerevisiae defined categories of PTEN N-terminal mutations with distinct PIP3 phosphatase and nuclear accumulation properties. Noticeably, most tumor-related mutations that lost PIP3 phosphatase activity also displayed impaired nuclear localization. Cell proliferation and soft-agar colony formation analysis in mammalian cells of mutations with distinctive nuclear accumulation and catalytic activity patterns suggested a contribution of both properties to PTEN tumor suppressor activity. Our functional dissection of the PTEN N-terminus provides the basis for a systematic analysis of tumor-related and experimentally engineered PTEN mutations.