Browsing by Author "Marques, Rita"
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- Identification of mTOR and AGO1 IRES trans-acting factorsPublication . Marques, Rita; Lacerda, Rafaela; Romão, LuísaCancer is the second leading cause of death globally; therefore, its study is crucial to discover new therapies. Under stress, the regular process of protein synthesis (canonical translation) is impaired, while a back-up mechanism mediated by internal ribosome entry sites (IRES) continues to function, allowing the synthesis of proteins that maintain cellular viability. This also happens in cancer cells, contributing for their survival and consequent tumorigenesis. IRES-mediated translation and its regulation by IRES trans-acting factors (ITAFs) has been correlated to metastasis and chemotherapeutic drug resistance. Therefore, our main goal was to validate ITAFs and assess their significance in cancer onset, thus becoming candidates as novel therapeutic targets. A bicistronic reporter system, which contains a first cistron translated via canonical translation and a second one translated by IRES of mTOR1 and AGO12 was used to test IRES-driven translation initiation activity. Experiments were carried out in which several proteins (hnRNPs) were silenced by specific siRNAs to analyse their function as ITAFs of mTOR and AGO1 IRESs. Also, distinct drugs were applied to simulate endoplasmic reticulum (ER) or hypoxia stress, to evaluate their effect on IRES activity. The relative IRES activity was assessed by luminescence tests and the protein levels by Western blot. In general, knockdown of hnRNPK and hnRNPU seems to decrease the IRES activity by ~60% and ~30% respectively, while hnRNPC knockdown does not show a significant effect. Regarding the ER stress, hnRNPK knockdown seems to decrease even more the IRES activity, while hnRNPU depletion induces a significant increase. On the other hand, in hypoxia, the hnRNPs knockdowns do not significantly affect IRES activity. These results indicate that hnRNPK and hnRNPU may function as ITAFs of mTOR and AGO1 IRES activity in cells under ER stress. Our data can be decisive for a better understanding of carcinogenesis and suggest new therapeutic targets for cancer treatment. 1. Marques-Ramos, A., et.al. 2017. RNA. 23, 1712-1728 2. Lacerda, R. 2016. Faculdade de Ciências e Tecnologia da Universidade NOVA de Lisboa
- Internal Ribosome Entry Site (IRES)-Mediated Translation and Its Potential for Novel mRNA-Based Therapy DevelopmentPublication . Marques, Rita; Lacerda, Rafaela; Romão, LuísaMany conditions can benefit from RNA-based therapies, namely, those targeting internal ribosome entry sites (IRESs) and their regulatory proteins, the IRES trans-acting factors (ITAFs). IRES-mediated translation is an alternative mechanism of translation initiation, known for maintaining protein synthesis when canonical translation is impaired. During a stress response, it contributes to cell reprogramming and adaptation to the new environment. The relationship between IRESs and ITAFs with tumorigenesis and resistance to therapy has been studied in recent years, proposing new therapeutic targets and treatments. In addition, IRES-dependent translation initiation dysregulation is also related to neurological and cardiovascular diseases, muscular atrophies, or other syndromes. The participation of these structures in the development of such pathologies has been studied, yet to a far lesser extent than in cancer. Strategies involving the disruption of IRES-ITAF interactions or the modification of ITAF expression levels may be used with great impact in the development of new therapeutics. In this review, we aim to comprehend the current data on groups of human pathologies associated with IRES and/or ITAF dysregulation and their application in the designing of new therapeutic approaches using them as targets or tools. Thus, we wish to summarise the evidence in the field hoping to open new promising lines of investigation toward personalised treatments.
- Internal Ribosome Entry Site-Dependent Translation Dysregulation-Related DiseasesPublication . Marques, Rita; Lacerda, Rafaela; Romão, LuísaInternal ribosome entry site (IRES)-mediated translation is an alternative mechanism of translation initiation, known for maintaining protein synthesis when canonical translation is impaired. During a stress response, it contributes to cell reprogramming and adaptation to the new environment.
- Projeto Envelhecimento e ViolênciaPublication . Gil, Ana Paula; Santos, Ana João; Nunes, Baltazar; Marques, Rita; Nicolau, Rita; Fernandes, Ana Alexandre; Gomes, Inês; Faria, Paula Lobato; Lázaro, João; Oliveira, Maria; Santos, César; Nuno, Duarte; Rasgado, Sofia; Pargana, GlóriaO aumento da violência nas suas diferentes formas tem sido reconhecido por várias organizações internacionais (WHO, ONU, EU) como um dos mais graves problemas de saúde pública no emergir do século XXI, constituindo uma prioridade das suas agendas políticas, nomeadamente no desenvolvimento de investigação (instrumentos de deteção, avaliação e intervenção) que permitam conter o fenómeno, no quadro da vida familiar. Na declaração de Toronto de 2002, a OMS define violência e maus-tratos a pessoas idosas como “qualquer acto isolado ou repetido, ou a ausência de acção apropriada, que ocorre em qualquer relacionamento em que haja uma expectativa de confiança, e que cause dano, ou incómodo a uma pessoa idosa. Estes actos podem ser de vários tipos: físico, psicológico/emocional, sexual, financeiro ou, simplesmente, reflectir actos de negligência intencional, ou por omissão”[1]. Os dados sobre a prevalência global da violência contra as pessoas idosas, em contexto familiar, têm permitido em alguns países conhecer a amplitude do fenómeno. As estimativas das taxas globais de prevalência da violência (Quadro 1) variaram entre 0.8% e 18.4%. Esta oscilação das estimativas depende quer da sua conceptualização (da sua definição, dos tipos considerados), do perfil de agressor (tipo de relação), da própria vítima (>60 anos, >65 anos ou 65-84 anos), quer das metodologias adotadas (inquéritos via telefone ou presenciais).
- Public health policy and legislation instruments and tools: an updated review and proposal for further researchPublication . Matias Dias, Carlos; Marques, Rita; Ruseva, Maria; Nurse, Joanna; Dias, CasimiroThis document reviews the current policy and legislation instruments and tools in place for delivering public health operations in the WHO European Region. It aims to underpin and complement the European Action Plan for Strengthening Public Health Capacities and Services (EAP). It provides initial findings on the wide spectrum of legal and policy frameworks at regional and global levels discovered by mapping the available public health instruments and tools across 10 essential public health operations (EPHOs). The main findings are that at the global level legally binding instruments and tools are mainly concentrated in EPHO 3 (health protection) with 306 tools, EPHO 4 (health promotion) with 31 and EPHO 6 (governance) with 41. This corresponds to more than 90% of the total number of public health tools. However, there were only 2 tools for EPHO 5 (disease prevention), 3 for EPHO 7 (workforce) and 1 for EPHO 8 (organizational structures and financing). No legally binding tools were found for EPHO 9 (communication) and EPHO 10 (research). For EPHO 1 (surveillance) and EPHO 2 (response to health hazards and emergencies), there is a more balanced use of both legally and nonlegally binding tools. More evidence is needed on the cost–effectiveness of such instruments and tools. In addition, there is a need for greater advocacy, with a balance of regulation and persuasion, on what already exists – such as “best buy” interventions for noncommunicable diseases (NCDs) and the WHO Framework Convention on Tobacco Control (FCTC) – as well as a need to strengthen approaches to intersectoral governance.