29 results on '"Talotta, F"'
Search Results
2. Heterodimerization with Fra-1 cooperates with the ERK pathway to stabilize c-Jun in response to the RAS oncoprotein
- Author
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Talotta, F, Mega, T, Bossis, G, Casalino, L, Basbous, J, Jariel-Encontre, I, Piechaczyk, M, and Verde, P
- Published
- 2010
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3. An autoregulatory loop mediated by miR-21 and PDCD4 controls the AP-1 activity in RAS transformation
- Author
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Talotta, F, Cimmino, A, Matarazzo, M R, Casalino, L, De Vita, G, D'Esposito, M, Di Lauro, R, and Verde, P
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- 2009
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4. A direct link between expression of urokinase plasminogen activator receptor, growth rate and oncogenic transformation in mouse embryonic fibroblasts
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Mazzieri, R, Furlan, F, D'Alessio, S, Zonari, E, Talotta, F, Verde, P, and Blasi, F
- Published
- 2007
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5. miR-340 inhibits tumor cell proliferation and induces apoptosis by targeting multiple negative regulators of p27 in non-small cell lung cancer
- Author
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Fernandez, S, primary, Risolino, M, additional, Mandia, N, additional, Talotta, F, additional, Soini, Y, additional, Incoronato, M, additional, Condorelli, G, additional, Banfi, S, additional, and Verde, P, additional
- Published
- 2014
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6. An autoregulatory loop mediated by miR-21 and PDCD4 controls the AP-1 activity in RAS transformation
- Author
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Talotta, F, primary, Cimmino, A, additional, Matarazzo, M R, additional, Casalino, L, additional, De Vita, G, additional, D'Esposito, M, additional, Di Lauro, R, additional, and Verde, P, additional
- Published
- 2008
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7. A direct link between expression of urokinase plasminogen activator receptor, growth rate and oncogenic transformation in mouse embryonic fibroblasts
- Author
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Mazzieri, R, primary, Furlan, F, additional, D'Alessio, S, additional, Zonari, E, additional, Talotta, F, additional, Verde, P, additional, and Blasi, F, additional
- Published
- 2006
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8. miR-340 inhibits tumor cell proliferation and induces apoptosis by targeting multiple negative regulators of p27 in non-small cell lung cancer
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Mariarosaria Incoronato, Maurizio Risolino, Sandro Banfi, Serena Fernandez, Francesco Talotta, Pasquale Verde, Nadia Mandia, Ylermi Soini, Gerolama Condorelli, Fernandez, S, Risolino, M, Mandia, N, Talotta, F, Soini, Y, Incoronato, M, Condorelli, G, Banfi, Sandro, Verde, P., Condorelli, Gerolama, and Banfi, S
- Subjects
Cancer Research ,RHOA ,Lung Neoplasms ,Adenocarcinoma of Lung ,Apoptosis ,RNA-Binding Protein ,Adenocarcinoma ,NSCLC ,Article ,Downregulation and upregulation ,Genetic ,Cyclin-dependent kinase ,Pumilio ,Cell Movement ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,microRNA ,Genetics ,medicine ,Humans ,ROCK1 ,Molecular Biology ,Cell Proliferation ,biology ,Cell growth ,Medicine (all) ,Cell Cycle ,Cancer ,RNA-Binding Proteins ,Apoptosi ,p27 ,MicroRNA ,Cell cycle ,medicine.disease ,Cell biology ,Up-Regulation ,Lung Neoplasm ,MicroRNAs ,miR-340 ,biology.protein ,SKP2 ,Cyclin-Dependent Kinase Inhibitor p27 ,Human - Abstract
MicroRNAs (miRNAs) control cell cycle progression by targeting the transcripts encoding for cyclins, CDKs and CDK inhibitors, such as p27(KIP1) (p27). p27 expression is controlled by multiple transcriptional and posttranscriptional mechanisms, including translational inhibition by miR-221/222 and posttranslational regulation by the SCF(SKP2) complex. The oncosuppressor activity of miR-340 has been recently characterized in breast, colorectal and osteosarcoma tumor cells. However, the mechanisms underlying miR-340-induced cell growth arrest have not been elucidated. Here, we describe miR-340 as a novel tumor suppressor in non-small cell lung cancer (NSCLC). Starting from the observation that the growth-inhibitory and proapoptotic effects of miR-340 correlate with the accumulation of p27 in lung adenocarcinoma and glioblastoma cells, we have analyzed the functional relationship between miR-340 and p27 expression. miR-340 targets three key negative regulators of p27. The miR-340-mediated inhibition of both Pumilio family RNA-binding proteins (PUM1 and PUM2), required for the miR-221/222 interaction with the p27 3'-UTR, antagonizes the miRNA-dependent downregulation of p27. At the same time, miR-340 induces the stabilization of p27 by targeting SKP2, the key posttranslational regulator of p27. Therefore, miR-340 controls p27 at both translational and posttranslational levels. Accordingly, the inhibition of either PUM1 or SKP2 partially recapitulates the miR-340 effect on cell proliferation and apoptosis. In addition to the effect on tumor cell proliferation, miR-340 also inhibits intercellular adhesion and motility in lung cancer cells. These changes correlate with the miR-340-mediated inhibition of previously validated (MET and ROCK1) and potentially novel (RHOA and CDH1) miR-340 target transcripts. Finally, we show that in a small cohort of NSCLC patients (n=23), representative of all four stages of lung cancer, miR-340 expression inversely correlates with clinical staging, thus suggesting that miR-340 downregulation contributes to the disease progression.
- Published
- 2015
9. An autoregulatory loop mediated by miR-21 and PDCD4 controls the AP-1 activity in RAS transformation
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R Di Lauro, G De Vita, Maria R. Matarazzo, Maurizio D'Esposito, Amelia Cimmino, Pasquale Verde, Laura Casalino, Francesco Talotta, Talotta, F., Cimmino, A., Matarazzo, M. R., Casalino, L., DE VITA, Gabriella, D'Esposito, M., DI LAURO, Roberto, and Verde, P.
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PTEN ,Cancer Research ,C-JUN ,Tumor suppressor gene ,Cell Survival ,Proto-Oncogene Proteins c-jun ,Thyroid Gland ,medicine.disease_cause ,Downregulation and upregulation ,Cell Line, Tumor ,microRNA ,MICRORNA-21 TARGETS ,TUMORIGENESIS ,Genetics ,medicine ,BREAST-CANCER ,Gene silencing ,Animals ,Homeostasis ,Humans ,TUMOR-SUPPRESSOR PDCD4 ,MESSENGER-RNAS ,Molecular Biology ,Transcription factor ,GENE-EXPRESSION ,PDCD4 ,biology ,PTEN Phosphohydrolase ,Oncomir ,ONCOGENIC RAS ,AP-1 ,Rats ,Transcription Factor AP-1 ,TRANSCRIPTION FACTORS ,MicroRNAs ,Cell Transformation, Neoplastic ,CELLS ,Cancer research ,biology.protein ,ras Proteins ,miR-21 ,Carcinogenesis ,Apoptosis Regulatory Proteins ,Proto-Oncogene Proteins c-fos ,RAS - Abstract
The transcription factor AP-1 plays key roles in tumorigenesis, by regulating a variety of protein-coding genes, implicated in multiple hallmarks of cancer. Among non-coding genes, no AP-1 target has been described yet in tumorigenesis. MicroRNAs (miRNAs) are negative post-transcriptional regulators of protein-coding genes. miRNA expression signatures are highly relevant in cancer and several tumor-associated miRNAs (oncomirs) play critical roles in oncogenesis. Here, we show that the miRNA miR-21, which represents the most frequently upregulated oncomir in solid tumors, is induced by AP-1 in response to RAS. By analyzing validated miR-21 targets, we have found that the tumor suppressors PTEN and PDCD4 are downregulated by RAS in an AP-1- and miR-21-dependent fashion. We further show that, given the role of PDCD4 as negative regulator of AP-1, the miR-21-mediated downregulation of PDCD4 is essential for the maximal induction of AP-1 activity in response to RAS. Our data reveal a novel mechanism of positive autoregulation of the AP-1 complex in RAS transformation and disclose the function of oncomirs as critical targets and regulators of AP-1 in tumorigenesis.
- Published
- 2008
10. FRA-1 as a Regulator of EMT and Metastasis in Breast Cancer.
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Casalino L, Talotta F, Matino I, and Verde P
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- Animals, Humans, Cell Line, Tumor, Cell Movement, Disease Models, Animal, Epithelial-Mesenchymal Transition genetics, Gene Expression Regulation, Neoplastic, Neoplasm Metastasis, Transcription Factor AP-1 metabolism, Tumor Microenvironment, MicroRNAs genetics, Triple Negative Breast Neoplasms pathology
- Abstract
Among FOS-related components of the dimeric AP-1 transcription factor, the oncoprotein FRA-1 (encoded by FOSL1 ) is a key regulator of invasion and metastasis. The well-established FRA-1 pro-invasive activity in breast cancer, in which FOSL1 is overexpressed in the TNBC (Triple Negative Breast Cancer)/basal subtypes, correlates with the FRA-1-dependent transcriptional regulation of EMT (Epithelial-to-Mesenchymal Transition). After summarizing the major findings on FRA-1 in breast cancer invasiveness, we discuss the FRA-1 mechanistic links with EMT and cancer cell stemness, mediated by transcriptional and posttranscriptional interactions between FOSL1 /FRA-1 and EMT-regulating transcription factors, miRNAs, RNA binding proteins and cytokines, along with other target genes involved in EMT. In addition to the FRA-1/AP-1 effects on the architecture of target promoters, we discuss the diagnostic and prognostic significance of the EMT-related FRA-1 transcriptome, along with therapeutic implications. Finally, we consider several novel perspectives regarding the less explored roles of FRA-1 in the tumor microenvironment and in control of the recently characterized hybrid EMT correlated with cancer cell plasticity, stemness, and metastatic potential. We will also examine the application of emerging technologies, such as single-cell analyses, along with animal models of TNBC and tumor-derived CTCs and PDXs (Circulating Tumor Cells and Patient-Derived Xenografts) for studying the FRA-1-mediated mechanisms in in vivo systems of EMT and metastasis.
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- 2023
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11. Adiabatic and Nonadiabatic Dynamics with Interacting Quantum Trajectories.
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Dupuy L, Talotta F, Agostini F, Lauvergnat D, Poirier B, and Scribano Y
- Abstract
We present a quantum dynamics method based on the propagation of interacting quantum trajectories to describe both adiabatic and nonadiabatic processes within the same formalism. The idea originates from the work of Poirier [ Chem. Phys. 2010, 370, 4-14] and Schiff and Poirier [ J. Chem. Phys. 2012, 136, 031102] on quantum dynamics without wavefunctions. It consists of determining the quantum force arising in the Bohmian hydrodynamic formulation of quantum dynamics using only information about quantum trajectories. The particular time-dependent propagation scheme proposed here results in very stable dynamics. Its performance is discussed by applying the method to analytical potentials in the adiabatic regime, and by combining it with the exact factorization method in the nonadiabatic regime.
- Published
- 2022
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12. Describing the photo-isomerization of a retinal chromophore model with coupled and quantum trajectories.
- Author
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Talotta F, Lauvergnat D, and Agostini F
- Subjects
- Isomerism, Retina, Electrons, Quantum Theory
- Abstract
The exact factorization of the electron-nuclear wavefunction is applied to the study of photo-isomerization of a retinal chromophore model. We describe such an ultrafast nonadiabatic process by analyzing the time-dependent potentials of the theory and by mimicking nuclear dynamics with quantum and coupled trajectories. The time-dependent vector and scalar potentials are the signature of the exact factorization, as they guide nuclear dynamics by encoding the complete electronic dynamics and including excited-state effects. Analysis of the potentials is, thus, essential-when possible-to predict the time-dependent behavior of the system of interest. In this work, we employ the exact time-dependent potentials, available for the numerically exactly solvable model used here, to propagate quantum nuclear trajectories representing the isomerization reaction of the retinal chromophore. The quantum trajectories are the best possible trajectory-based description of the reaction when using the exact-factorization formalism and, thus, allow us to assess the performance of the coupled-trajectory, fully approximate schemes derived from the exact-factorization equations.
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- 2022
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13. The Fra-1/AP-1 Oncoprotein: From the "Undruggable" Transcription Factor to Therapeutic Targeting.
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Casalino L, Talotta F, Cimmino A, and Verde P
- Abstract
The genetic and epigenetic changes affecting transcription factors, coactivators, and chromatin modifiers are key determinants of the hallmarks of cancer. The acquired dependence on oncogenic transcriptional regulators, representing a major determinant of cancer cell vulnerability, points to transcription factors as ideal therapeutic targets. However, given the unavailability of catalytic activities or binding pockets for small-molecule inhibitors, transcription factors are generally regarded as undruggable proteins. Among components of the AP-1 complex, the FOS-family transcription factor Fra-1, encoded by FOSL1 , has emerged as a prominent therapeutic target. Fra-1 is overexpressed in most solid tumors, in response to the BRAF-MAPK, Wnt-beta-catenin, Hippo-YAP, IL-6-Stat3, and other major oncogenic pathways. In vitro functional analyses, validated in onco-mouse models and corroborated by prognostic correlations, show that Fra-1-containing dimers control tumor growth and disease progression. Fra-1 participates in key mechanisms of cancer cell invasion, Epithelial-to-Mesenchymal Transition, and metastatic spreading, by driving the expression of EMT-inducing transcription factors, cytokines, and microRNAs. Here we survey various strategies aimed at inhibiting tumor growth, metastatic dissemination, and drug resistance by interfering with Fra-1 expression, stability, and transcriptional activity. We summarize several tools aimed at the design and tumor-specific delivery of Fra-1/AP-1-specific drugs. Along with RNA-based therapeutics targeting the FOSL1 gene, its mRNA, or cognate regulatory circRNAs, we will examine the exploitation of blocking peptides, small molecule inhibitors, and innovative Fra-1 protein degraders. We also consider the possible caveats concerning Fra-1 inhibition in specific therapeutic contexts. Finally, we discuss a recent suicide gene therapy-based approach, aimed at selectively killing the Fra-1-overexpressing neoplastic cells.
- Published
- 2022
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14. Immunogenicity of a new gorilla adenovirus vaccine candidate for COVID-19.
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Capone S, Raggioli A, Gentile M, Battella S, Lahm A, Sommella A, Contino AM, Urbanowicz RA, Scala R, Barra F, Leuzzi A, Lilli E, Miselli G, Noto A, Ferraiuolo M, Talotta F, Tsoleridis T, Castilletti C, Matusali G, Colavita F, Lapa D, Meschi S, Capobianchi M, Soriani M, Folgori A, Ball JK, Colloca S, and Vitelli A
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Animals, Antibodies, Neutralizing immunology, Antibodies, Viral immunology, Cell Line, Cell Line, Tumor, Female, Genetic Vectors immunology, Gorilla gorilla virology, HEK293 Cells, HeLa Cells, Humans, Macaca, Male, Mice, Mice, Inbred BALB C, Middle Aged, Pandemics prevention & control, Young Adult, Adenoviridae immunology, Adenovirus Vaccines immunology, COVID-19 immunology, COVID-19 Vaccines immunology, Gorilla gorilla immunology, Immunogenicity, Vaccine immunology, SARS-CoV-2 immunology
- Abstract
The coronavirus disease 2019 (COVID-19) pandemic caused by the emergent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) threatens global public health, and there is an urgent need to develop safe and effective vaccines. Here, we report the generation and the preclinical evaluation of a novel replication-defective gorilla adenovirus-vectored vaccine encoding the pre-fusion stabilized Spike (S) protein of SARS-CoV-2. We show that our vaccine candidate, GRAd-COV2, is highly immunogenic both in mice and macaques, eliciting both functional antibodies that neutralize SARS-CoV-2 infection and block Spike protein binding to the ACE2 receptor, and a robust, T helper (Th)1-dominated cellular response. We show here that the pre-fusion stabilized Spike antigen is superior to the wild type in inducing ACE2-interfering, SARS-CoV-2-neutralizing antibodies. To face the unprecedented need for vaccine manufacturing at a massive scale, different GRAd genome deletions were compared to select the vector backbone showing the highest productivity in stirred tank bioreactors. This preliminary dataset identified GRAd-COV2 as a potential COVID-19 vaccine candidate, supporting the translation of the GRAd-COV2 vaccine in a currently ongoing phase I clinical trial (ClinicalTrials.gov: NCT04528641)., Competing Interests: Declaration of interests S. Capone, A.R., M.G., S.B., A.S., A.M.C., R.S., F.B., A. Leuzzi, E.L., G. Miselli, A.N., M.F., F.T., M.S., A.F., S. Colloca, and A.V. are employees of ReiThera Srl. A.F. and S. Colloca are also shareholders of Keires AG. A. Lahm is a consultant for ReiThera Srl. S. Colloca, A. Lahm, A.R., and A.V. are inventors of the patent application number 20183515.4, titled “Gorilla Adenovirus Nucleic Acid- and Amino Acid-Sequences, Vectors Containing Same, and Uses Thereof.” The other authors declare no competing interests., (Copyright © 2021 The American Society of Gene and Cell Therapy. All rights reserved.)
- Published
- 2021
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15. Electronic Structure and Excited States of the Collision Reaction O( 3 P) + C 2 H 4 : A Multiconfigurational Perspective.
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Talotta F, Morisset S, Rougeau N, Lauvergnat D, and Agostini F
- Abstract
We present a study of the O(
3 P) + C2 H4 scattering reaction, a process that takes place in the interstellar medium and is of relevance in atmospheric chemistry as well. A comprehensive investigation of the electronic properties of the system has been carried out based on multiconfigurational ab initio CASSCF/CASPT2 calculations, using a robust and consistent active space that can deliver accurate potential energy surfaces in the key regions visited by the system. The paper discloses detailed description of the primary reaction pathways and the relevant singlet and triplet excited states at the CASSCF and CASPT2 level, including an accurate description of the critical configurations, such as minima and transition states. The chosen active space and the CASSCF/CASPT2 computational protocol are assessed against coupled-cluster calculations to further check the stability and reliability of the entire multiconfigurational procedure.- Published
- 2021
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16. Early Relaxation Dynamics in the Photoswitchable Complex trans-[RuCl(NO)(py) 4 ] 2 .
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Talotta F, Boggio-Pasqua M, and González L
- Abstract
The design of photoswitchable transition metal complexes with tailored properties is one of the most important challenges in chemistry. Studies explaining the underlying mechanisms are, however, scarce. Herein, the early relaxation dynamics towards NO photoisomerization in trans-[RuCl(NO)(py)
4 ]2+ is elucidated by means of non-adiabatic dynamics, which provided time-resolved information and branching ratios. Three deactivation mechanisms (I, II, III) in the ratio 3:2:4 were identified. Pathways I and III involve ultrafast intersystem crossing and internal conversion, whereas pathway II involves only internal conversion., (© 2020 The Authors. Published by Wiley-VCH GmbH.)- Published
- 2020
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17. Quantum Trajectories for the Dynamics in the Exact Factorization Framework: A Proof-of-Principle Test.
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Talotta F, Agostini F, and Ciccotti G
- Abstract
In the framework of the exact factorization of the time-dependent electron-nuclear wave function, we investigate the possibility of solving the nuclear time-dependent Schrödinger equation based on trajectories. The nuclear equation is separated in a Hamilton-Jacobi equation for the phase of the wave function, and a continuity equation for its (squared) modulus. For illustrative adiabatic and nonadiabatic one-dimensional models, we implement a procedure to follow the evolution of the nuclear density along the characteristics of the Hamilton-Jacobi equation. Those characteristics are referred to as quantum trajectories, since they are generated via ordinary differential equations similar to Hamilton's equations, but including the so-called quantum potential, and they can be used to reconstruct exactly the quantum-mechanical nuclear wave function, provided infinite initial conditions are propagated in time.
- Published
- 2020
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18. Internal Conversion and Intersystem Crossing with the Exact Factorization.
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Talotta F, Morisset S, Rougeau N, Lauvergnat D, and Agostini F
- Abstract
We present a detailed derivation of the generalized coupled-trajectory mixed quantum-classical (G-CT-MQC) algorithm based on the exact-factorization equations. The ultimate goal is to propose an algorithm that can be employed for molecular dynamics simulations of nonradiative phenomena, as the spin-allowed internal conversions and the spin-forbidden intersystem crossings. Internal conversions are nonadiabatic processes driven by the kinetic coupling between electronic states, whereas intersystem crossings are mediated by the spin-orbit coupling. In this paper, we discuss computational issues related to the suitable representation for electronic dynamics and the different natures of kinetic and spin-orbit coupling. Numerical studies on model systems allow us to test the performance of the G-CT-MQC algorithm in different situations.
- Published
- 2020
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19. CASPT2 Potential Energy Curves for NO Dissociation in a Ruthenium Nitrosyl Complex.
- Author
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Talotta F, González L, and Boggio-Pasqua M
- Subjects
- Models, Molecular, Molecular Structure, Nitric Oxide chemistry, Nitroso Compounds chemistry, Organometallic Compounds chemistry, Photochemistry, Quantum Theory, Ruthenium chemistry
- Abstract
Ruthenium nitrosyl complexes are fascinating photoactive compounds showing complex photoreactivity, such as N→O linkage photoisomerism and NO photorelease. This dual photochemical behavior has been the subject of many experimental studies in order to optimize these systems for applications as photoswitches or therapeutic agents for NO delivery. However, despite recent experimental and computational studies along this line, the underlying photochemical mechanisms still need to be elucidated for a more efficient design of these systems. Here, we present a theoretical contribution based on the calculations of excited-state potential energy profiles for NO dissociation in the prototype trans -[RuCl(NO)(py)
4 ]2+ complex at the complete active space second-order perturbation theory (CASPT2). The results point to a sequential two-step photon absorption photorelease mechanism coupled to partial photoisomerization to a side-on intermediate, in agreement with previous density functional theory calculations.- Published
- 2020
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20. The nuclear oncoprotein Fra-1: a transcription factor knocking on therapeutic applications' door.
- Author
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Talotta F, Casalino L, and Verde P
- Subjects
- Animals, Cell Proliferation genetics, Disease Models, Animal, Epithelial-Mesenchymal Transition genetics, Gene Expression Regulation, Neoplastic genetics, Humans, Mice, MicroRNAs genetics, Neoplasm Metastasis pathology, Protein Processing, Post-Translational genetics, Tumor Microenvironment genetics, Tumor Suppressor Protein p53 metabolism, Cell Transformation, Neoplastic genetics, Neoplasms genetics, Neoplasms pathology, Proto-Oncogene Proteins c-fos genetics
- Abstract
Among the FOS-related members of the AP-1 dimeric complex, the transcription factor Fra-1, encoded by FOSL1, is crucially involved in human tumor progression and metastasis, thus representing a promising therapeutic target. Here we review the state of the art and discuss the emerging topics and perspectives on FOSL1 and its gene product. First, we summarize the present knowledge on the FOSL1 transcriptional and epigenetic controls, driving Fra-1 accumulation in a variety of human solid tumors. We also present a model on the regulatory interactions between Fra-1, p53, and miRNAs. Then, we outline the multiple roles of Fra-1 posttranslational modifications and transactivation mechanisms of select Fra-1 target genes. In addition to summarizing the Fra-1-dependent gene networks controlling proliferation, survival, and epithelial-mesenchymal transitions (EMT) in multiple cancer cell types, we highlight the roles played by Fra-1 in nonneoplastic cell populations recruited to the tumor microenvironment, and in mouse models of tumorigenesis. Next, we review the prognostic power of the Fra-1-associated gene signatures, and envisage potential strategies aimed at Fra-1 therapeutic inhibition. Finally, we discuss several recent reports showing the emerging roles of Fra-1 in the mechanisms of both resistance and addiction to targeted therapies.
- Published
- 2020
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21. Spin-Orbit Interactions in Ultrafast Molecular Processes.
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Talotta F, Morisset S, Rougeau N, Lauvergnat D, and Agostini F
- Abstract
We investigate spin-orbit interactions in ultrafast molecular processes employing the exact factorization of the electron-nuclear wave function. We revisit the original derivation by including spin-orbit coupling, and show how the dynamics driven by the time-dependent potential energy surface alleviates inconsistencies arising from different electronic representations. We propose a novel trajectory-based scheme to simulate spin-forbidden non-radiative processes, and we show its performance in the treatment of excited-state dynamics where spin-orbit effects couple different spin multiplets.
- Published
- 2020
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22. Linkage Photoisomerization Mechanism in a Photochromic Ruthenium Nitrosyl Complex: New Insights from an MS-CASPT2 Study.
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Talotta F, Heully JL, Alary F, Dixon IM, González L, and Boggio-Pasqua M
- Abstract
The N → O linkage photoisomerization mechanism in a ruthenium nitrosyl complex, [RuCl(NO)(py)
4 ]2+ , for which a quasicomplete photoconversion between the stable nitrosyl (N-bonded) and metastable isonitrosyl (O-bonded) isomers has been observed under continuous irradiation of the crystal at 473 nm ( Cormary et al. Acta Cryst. B 2009 , 65 , 612 - 623 ), is investigated using multiconfigurational second-order perturbation theory (CASPT2). The results support efficient intersystem crossing pathways from the initially excited singlet states to the lowest triplet excited state of metal-to-ligand charge transfer character (3 MLCT). The topology of the involved potential energy surfaces corroborates a complex sequential two-photon photoisomerization mechanism involving nonadiabatic processes in agreement with experimental observations and previous density functional theory calculations.- Published
- 2017
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23. A Theoretical Study of the N to O Linkage Photoisomerization Efficiency in a Series of Ruthenium Mononitrosyl Complexes.
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García JS, Talotta F, Alary F, Dixon IM, Heully JL, and Boggio-Pasqua M
- Subjects
- Coordination Complexes chemistry, Isomerism, Kinetics, Ligands, Light, Models, Molecular, Molecular Structure, Quantum Theory, Thermodynamics, Coordination Complexes radiation effects, Nitric Oxide chemistry, Ruthenium chemistry
- Abstract
Ruthenium nitrosyl complexes are fascinating versatile photoactive molecules that can either undergo NO linkage photoisomerization or NO photorelease. The photochromic response of three ruthenium mononitrosyl complexes, trans -[RuCl(NO)(py)₄]
2+ , trans -[RuBr(NO)(py)₄]2+ , and trans -(Cl,Cl)[RuCl₂(NO)(tpy)]⁺, has been investigated using density functional theory and time-dependent density functional theory. The N to O photoisomerization pathways and absorption properties of the various stable and metastable species have been computed, providing a simple rationalization of the photoconversion trend in this series of complexes. The dramatic decrease of the N to O photoisomerization efficiency going from the first to the last complex is mainly attributed to an increase of the photoproduct absorption at the irradiation wavelength, rather than a change in the photoisomerization pathways., Competing Interests: The authors declare no conflict of interest.- Published
- 2017
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24. Assessing Excited State Energy Gaps with Time-Dependent Density Functional Theory on Ru(II) Complexes.
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Atkins AJ, Talotta F, Freitag L, Boggio-Pasqua M, and González L
- Abstract
A set of density functionals coming from different rungs on Jacob's ladder is employed to evaluate the electronic excited states of three Ru(II) complexes. While most studies on the performance of density functionals compare the vertical excitation energies, in this work we focus on the energy gaps between the electronic excited states, of the same and different multiplicity. Excited state energy gaps are important for example to determine radiationless transition probabilities. Besides energies, a functional should deliver the correct state character and state ordering. Therefore, wave function overlaps are introduced to systematically evaluate the effect of different functionals on the character of the excited states. As a reference, the energies and state characters from multistate second-order perturbation theory complete active space (MS-CASPT2) are used. In comparison to MS-CASPT2, it is found that while hybrid functionals provide better vertical excitation energies, pure functionals typically give more accurate excited state energy gaps. Pure functionals are also found to reproduce the state character and ordering in closer agreement to MS-CASPT2 than the hybrid functionals.
- Published
- 2017
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25. Genetic variants modulating CRIPTO serum levels identified by genome-wide association study in Cilento isolates.
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Ruggiero D, Nappo S, Nutile T, Sorice R, Talotta F, Giorgio E, Bellenguez C, Leutenegger AL, Liguori GL, and Ciullo M
- Subjects
- Adult, Aged, Cell Movement genetics, Embryonic Development genetics, Epithelial-Mesenchymal Transition genetics, Female, GPI-Linked Proteins blood, Gene Expression Regulation, Humans, Intercellular Signaling Peptides and Proteins blood, Italy, Middle Aged, Neoplasm Proteins blood, Neoplasms blood, Transcription Factor AP-1 genetics, Transforming Growth Factor beta, Cell Proliferation genetics, GPI-Linked Proteins genetics, Genome-Wide Association Study, Intercellular Signaling Peptides and Proteins genetics, Neoplasm Proteins genetics, Neoplasms genetics
- Abstract
Cripto, the founding member of the EGF-CFC genes, plays an essential role in embryo development and is involved in cancer progression. Cripto is a GPI-anchored protein that can interact with various components of multiple signaling pathways, such as TGF-β, Wnt and MAPK, driving different processes, among them epithelial-mesenchymal transition, cell proliferation, and stem cell renewal. Cripto protein can also be cleaved and released outside the cell in a soluble and still active form. Cripto is not significantly expressed in adult somatic tissues and its re-expression has been observed associated to pathological conditions, mainly cancer. Accordingly, CRIPTO has been detected at very low levels in the plasma of healthy volunteers, whereas its levels are significantly higher in patients with breast, colon or glioblastoma tumors. These data suggest that CRIPTO levels in human plasma or serum may have clinical significance. However, very little is known about the variability of serum levels of CRIPTO at a population level and the genetic contribution underlying this variability remains unknown. Here, we report the first genome-wide association study of CRIPTO serum levels in isolated populations (n = 1,054) from Cilento area in South Italy. The most associated SNPs (p-value<5*10-8) were all located on chromosome 3p22.1-3p21.3, in the CRIPTO gene region. Overall six CRIPTO associated loci were replicated in an independent sample (n = 535). Pathway analysis identified a main network including two other genes, besides CRIPTO, in the associated regions, involved in cell movement and proliferation. The replicated loci explain more than 87% of the CRIPTO variance, with 85% explained by the most associated SNP. Moreover, the functional analysis of the main associated locus identified a causal variant in the 5'UTR of CRIPTO gene which is able to strongly modulate CRIPTO expression through an AP-1-mediate transcriptional regulation.
- Published
- 2015
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26. Transcription factor PREP1 induces EMT and metastasis by controlling the TGF-β-SMAD3 pathway in non-small cell lung adenocarcinoma.
- Author
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Risolino M, Mandia N, Iavarone F, Dardaei L, Longobardi E, Fernandez S, Talotta F, Bianchi F, Pisati F, Spaggiari L, Harter PN, Mittelbronn M, Schulte D, Incoronato M, Di Fiore PP, Blasi F, and Verde P
- Subjects
- Adenocarcinoma genetics, Adenocarcinoma of Lung, Animals, Brain Neoplasms pathology, Brain Neoplasms secondary, Carcinoma, Non-Small-Cell Lung genetics, Cell Line, Tumor, Cell Movement drug effects, Cell Nucleus drug effects, Cell Nucleus metabolism, Cell Proliferation drug effects, DNA-Binding Proteins metabolism, Enhancer Elements, Genetic genetics, Gene Expression Regulation, Neoplastic drug effects, Humans, Introns genetics, Lung Neoplasms genetics, Mice, Models, Biological, Neoplasm Metastasis, Peptide Hydrolases metabolism, Pre-B-Cell Leukemia Transcription Factor 1, Protein Binding drug effects, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins c-fos metabolism, Smad3 Protein genetics, Survival Analysis, Transcription Factor AP-1 metabolism, Transcription, Genetic drug effects, Transforming Growth Factor beta pharmacology, Adenocarcinoma pathology, Carcinoma, Non-Small-Cell Lung pathology, Epithelial-Mesenchymal Transition drug effects, Epithelial-Mesenchymal Transition genetics, Homeodomain Proteins metabolism, Lung Neoplasms pathology, Signal Transduction drug effects, Signal Transduction genetics, Smad3 Protein metabolism, Transforming Growth Factor beta metabolism
- Abstract
Pre-B-cell leukemia homeobox (Pbx)-regulating protein-1 (Prep1) is a ubiquitous homeoprotein involved in early development, genomic stability, insulin sensitivity, and hematopoiesis. Previously we have shown that Prep1 is a haploinsufficient tumor suppressor that inhibits neoplastic transformation by competing with myeloid ecotropic integration site 1 for binding to the common heterodimeric partner Pbx1. Epithelial-mesenchymal transition (EMT) is controlled by complex networks of proinvasive transcription factors responsive to paracrine factors such as TGF-β. Here we show that, in addition to inhibiting primary tumor growth, PREP1 is a novel EMT inducer and prometastatic transcription factor. In human non-small cell lung cancer (NSCLC) cells, PREP1 overexpression is sufficient to trigger EMT, whereas PREP1 down-regulation inhibits the induction of EMT in response to TGF-β. PREP1 modulates the cellular sensitivity to TGF-β by inducing the small mothers against decapentaplegic homolog 3 (SMAD3) nuclear translocation through mechanisms dependent, at least in part, on PREP1-mediated transactivation of a regulatory element in the SMAD3 first intron. Along with the stabilization and accumulation of PBX1, PREP1 induces the expression of multiple activator protein 1 components including the proinvasive Fos-related antigen 1 (FRA-1) oncoprotein. Both FRA-1 and PBX1 are required for the mesenchymal changes triggered by PREP1 in lung tumor cells. Finally, we show that the PREP1-induced mesenchymal transformation correlates with significantly increased lung colonization by cells overexpressing PREP1. Accordingly, we have detected PREP1 accumulation in a large number of human brain metastases of various solid tumors, including NSCLC. These findings point to a novel role of the PREP1 homeoprotein in the control of the TGF-β pathway, EMT, and metastasis in NSCLC.
- Published
- 2014
- Full Text
- View/download PDF
27. Deciphering AP-1 function in tumorigenesis: fra-ternizing on target promoters.
- Author
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Verde P, Casalino L, Talotta F, Yaniv M, and Weitzman JB
- Subjects
- Animals, Gene Targeting methods, Humans, Neoplasm Proteins chemistry, Neoplasm Proteins genetics, Neoplasms chemistry, Neoplasms genetics, Proto-Oncogene Proteins c-fos chemistry, Proto-Oncogene Proteins c-fos genetics, Transcription Factor AP-1 chemistry, Transcription Factor AP-1 genetics, Neoplasm Proteins physiology, Neoplasms etiology, Neoplasms metabolism, Promoter Regions, Genetic physiology, Proto-Oncogene Proteins c-fos physiology, Transcription Factor AP-1 physiology
- Abstract
Multi-gene families of transcription factors pose a formidable challenge to molecular and functional analysis. Dissecting distinct functions for individual family members requires a combination of approaches in different cellular and animal models. The AP-1 transcription factor complex serves as a paradigm for understanding the dynamics of transcriptional regulation. Knockout, knockdown and transgenic strategies, inducible alleles, mutational analysis, chemical genetics, etc.; researchers have applied all the tricks of the trade to understand how AP-1 works. AP-1 refers to a mixture of dimers formed between members of the Jun, Fos and ATF families. The complexity of the AP-1 biological functions reflects the wide combinatorial diversity of its components. AP-1 has been linked to cancer and neoplastic transformation ever since the first jun and fos genes were cloned as cellular homologues of viral oncogenes twenty years ago. Because of the oncogenic or tumor suppressive activity exhibited by distinct Jun and Fos nuclear proteins depending on the cell context and the genetic background of the tumor, the AP-1 complex has been called a "double-edged sword" in tumorigenesis. The cumulating results over the last decade are finally leading to the identification of specific functions for individual AP-1 components and their contribution to neoplastic disease. Here, we focus on the Fra-1 protein in tumorigenesis, which offers an illustrative example of this helter-skelter voyage.
- Published
- 2007
- Full Text
- View/download PDF
28. Urokinase plasminogen activator receptor affects bone homeostasis by regulating osteoblast and osteoclast function.
- Author
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Furlan F, Galbiati C, Jorgensen NR, Jensen JE, Mrak E, Rubinacci A, Talotta F, Verde P, and Blasi F
- Subjects
- Animals, Base Sequence, Bone and Bones cytology, Bone and Bones diagnostic imaging, DNA Primers, Mice, Mice, Knockout, Organ Size, Receptors, Cell Surface genetics, Receptors, Urokinase Plasminogen Activator, Reverse Transcriptase Polymerase Chain Reaction, Tomography, X-Ray Computed, Bone and Bones physiology, Homeostasis physiology, Osteoblasts cytology, Osteoclasts cytology, Receptors, Cell Surface physiology
- Abstract
Unlabelled: The uPAR and its ligand uPA are expressed by both osteoblasts and osteoclasts. Their function in bone remodeling is unknown. We report that uPAR-lacking mice display increased BMD, increased osteogenic potential of osteoblasts, decreased osteoclasts formation, and altered cytoskeletal reorganization in mature osteoclasts., Introduction: Urokinase receptor (uPAR) is actively involved in the regulation of important cell functions, such as proliferation, adhesion, and migration. It was previously shown that the major players in bone remodeling, osteoblasts and osteoclasts, express uPAR and produce urokinase (uPA). The purpose of this study was to investigate the role of uPAR in bone remodeling., Materials and Methods: In vivo studies were performed in uPAR knockout (KO) and wildtype (WT) mice on a C57Bl6/SV129 (75:25) background. Bone mass was analyzed by pQCT. Excised tibias were subjected to mechanical tests. UPAR KO calvaria osteoblasts were characterized by proliferation assays, RT-PCR for important proteins secreted during differentiation, and immunoblot for activator protein 1 (AP-1) family members. In vitro osteoclast formation was tested with uPAR KO bone marrow monocytes in the presence of macrophage-colony stimulating factor (M-CSF) and RANKL. Phalloidin staining in osteoclasts served to study actin ring and podosome formation., Results: pQCT revealed increased bone mass in uPAR-null mice. Mechanical tests showed reduced load-sustaining capability in uPAR KO tibias. uPAR KO osteoblasts showed a proliferative advantage with no difference in apoptosis, higher matrix mineralization, and earlier appearance of alkaline phosphatase (ALP). Surface RANKL expression at different stages of differentiation was not altered. AP-1 components, such as JunB and Fra-1, were upregulated in uPAR KO osteoblasts, along with other osteoblasts markers. On the resorptive side, the number of osteoclasts formed in vitro from uPAR KO monocytes was decreased. Podosome imaging in uPAR KO osteoclasts revealed a defect in actin ring formation., Conclusions: The defective proliferation and differentiation of bone cells, coincident with both aberrant expression of transcription factors and cytoskeletal organization, are typical uPAR-dependent molecular phenotypes, and we have now shown their function in osteoblasts and osteoclasts function in vivo.
- Published
- 2007
- Full Text
- View/download PDF
29. Fra-1 promotes growth and survival in RAS-transformed thyroid cells by controlling cyclin A transcription.
- Author
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Casalino L, Bakiri L, Talotta F, Weitzman JB, Fusco A, Yaniv M, and Verde P
- Subjects
- Animals, Apoptosis, Cell Cycle Proteins metabolism, Cell Line, Transformed, Cell Proliferation, Cell Survival, Clone Cells, Cyclin A metabolism, Flow Cytometry, G2 Phase, Mitosis, Promoter Regions, Genetic genetics, Protein Binding, Proto-Oncogene Proteins c-fos biosynthesis, Proto-Oncogene Proteins c-fos genetics, Proto-Oncogene Proteins c-jun metabolism, RNA Interference, Rats, Transcriptional Activation genetics, Cyclin A genetics, Genes, ras, Proto-Oncogene Proteins c-fos metabolism, Thyroid Gland cytology, Thyroid Gland growth & development, Transcription, Genetic
- Abstract
Fra-1 is frequently overexpressed in epithelial cancers and implicated in invasiveness. We previously showed that Fra-1 plays crucial roles in RAS transformation in rat thyroid cells and mouse fibroblasts. Here, we report a novel role for Fra-1 as a regulator of mitotic progression in RAS-transformed thyroid cells. Fra-1 expression and phosphorylation are regulated during the cell cycle, peaking at G2/M. Knockdown of Fra-1 caused a proliferative block and apoptosis. Although most Fra-1-knockdown cells accumulated in G2, a fraction of cells entering M-phase underwent abortive cell division and exhibited hallmarks of genomic instability (micronuclei, lagging chromosomes and anaphase bridges). Furthermore, we established a link between Fra-1 and the cell-cycle machinery by identifying cyclin A as a novel transcriptional target of Fra-1. During the cell cycle, Fra-1 was recruited to the cyclin A gene (ccna2) promoter, binding to previously unidentified AP-1 sites and the CRE. Fra-1 also induced the expression of JunB, which in turn interacts with the cyclin A promoter. Hence, Fra-1 induction is important in thyroid tumorigenesis, critically regulating cyclin expression and cell-cycle progression.
- Published
- 2007
- Full Text
- View/download PDF
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