National Institute of Health Dr. Ricardo Jorge
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Assessment of mercury exposure in the first harmonized total diet study in Portugal
No full textO objetivo deste estudo foi estimar a exposição da população portuguesa ao metilmercúrio e mercúrio inorgânico, usando uma metodologia harmonizada de Estudos de Dieta Total (TDS), e avaliar o risco de exceder a Dose Semanal Admissível (DSA) (1,3 e 4 µg/kg de peso corporal/ semana, respetivamente). Amostras de alimentos representativas do padrão alimentar da população foram preparadas de acordo com os hábitos de consumo e analisadas para determinar o teor de mercúrio total. O metilmercúrio e o mercúrio inorgânico foram estimados a partir do mercúrio total, utilizando a abordagem conservadora da Autoridade Europeia para a Segurança dos Alimentos (EFSA) e a exposição aos mesmos foi estimada usando o Monte Carlo Risk Assessment (MCRA). A exposição dos adultos e idosos dos 18 aos 74 anos, expressa em µg/kg peso corporal/semana, ao metilmercúrio foi de 1,25 (média), 0,01 (mediana) e 5,45 (P95), enquanto ao mercúrio inorgânico foi de 0,37 (média), 0,15 (mediana) e 1,27 (P95). Dos indivíduos, 27,6% excederam a DSA, para o metilmercúrio, e 3,5% para o mercúrio inorgânico. Entre as mulheres em idade fértil (18-45 anos), a exposição média ao metilmercúrio foi de 1,13 µg/kg peso corporal/semana, com 25% excedendo a DSA. O bacalhau seco e a pescada foram os principais contribuintes para a ingestão de mercúrio.The aim of this study was to estimate the exposure of the Portuguese population to methylmercury and inorganic mercury using a harmonized Total Diet Study (TDS) methodology and to assess the risk of exceeding the Tolerable Weekly Intake (TWI) (1.3 and 4 µg/kg body weight/week, respectively). Food samples representative of the population’s diet were prepared as consumed and analysed for total mercury. The European Food Safety Authority’s (EFSA) conservative approach to estimating methylmercury and inorganic mercury was applied, and exposure was assessed using the Monte Carlo Risk Assessment (MCRA) software. The mean, median, and P95 exposure of adults and elderly from 18 to 74 years old to methylmercury was 1.25, 0.01, and 5.45 µg/kg body weight/week, respectively, while exposure to inorganic mercury was 0.37, 0.15, and 1.27 µg/kg body weight/week. TWI was exceeded by 27.6% of the individuals for methylmercury and by 3.5% for inorganic mercury. Women of childbearing age (18–45 years) showed a mean exposure to methylmercury of 1.13 µg/kg body weight/week, with 25% exceeding the TWI. Cod and hake were the main contributors to mercury intake
Detection of Rickettsia in ticks using loop-mediated isothermal amplification (LAMP)
No full textObjectives: The objective of the study was to develop a Loop-mediated Isothermal Amplification (LAMP) assay for screening of Rickettsia species circulating in ticks using the citrate synthase gene (gltA). The LAMP assay employed portable visualisation methods, making the assay more field-suitable. Furthermore, prior methods have not used gltA as the target, despite proven success in Polymerase Chain Reaction (PCR) methods. Methods: Using an alignment of 72 DNA sequences (comprised of 21 Rickettsia species) from GenBank we designed a novel set of gltA LAMP primers. Evaluation used DNA from 12 Rickettsia species as positive controls (extracted from cultures or naturally infected ticks) alongside a panel of negative controls representing different bacterial species. Subsequently this assay was used to screen 295 Ixodes ricinus and 24 I. hexagonus ticks collected from the UK (including northern and southern England and northern Scotland). Results: LAMP successfully detected 11 out of 12 (91.7%) Rickettsia species, excluding Rickettsia akari. Among 319 ticks collected in the UK, three were positive for Rickettsia (0.9%). All three positives were I. ricinus ticks, while none of the 24 I. hexagonus ticks were positive. Results were confirmed using a published PCR method. Sanger sequencing of PCR amplicons generated for each positive tick showed that they were all R. helvetica. Conclusions: This study introduces a novel field-applicable LAMP protocol for efficient Rickettsia screening in ticks to better assess its prevalence and consequent health risks. Furthermore, this assay has proven suitability for rickettsial detection in I. ricinus ticks, which has been reported as unsuccessful in previous European studies.European Society of Clinical Microbiology and Infectious Disease
Acrylamide in cereals and cereal products: analytical method validation and preliminary results
No full textA reação de Maillard, responsável pela cor, sabor e aroma dos alimentos, também produz substâncias nocivas, como a acrilamida (AA). Esta amida insaturada forma-se quando alimentos ricos em hidratos de carbono, como pão, batatas e café, são cozinhados a temperaturas elevadas e humidade baixa. A União Europeia classificou a AA como carcinogénica (Categoria 1B), mutagénica (Categoria 1B) e tóxica para a reprodução (Categoria 2). O presente estudo visa validar um método para determinar AA em cereais e derivados e investigar a sua presença em diferentes variedades desses produtos. Utilizou-se a cromatografia líquida de ultra eficiência acoplada a um detetor de massa (UPLC-MS/MS) com ionização por electrospray positiva (ESI+ ) para detetar e quantificar a AA. O desempenho do método foi validado utilizando testes de avaliação externa da qualidade internacionais como testes de proficiência (FAPAS) e material de referência certificado (ERM-BD272). Avaliaram-se parâmetros como linearidade, limite de deteção (LD), limite de quantificação (LQ), precisão, exatidão e incerteza. Os LD e LQ foram de 0,40 µg/L e 1,22 µg/L, respetivamente, em conformidade com o Regulamento (UE) 2017/2158. A curva de calibração mostrou linearidade (R2 > 0,995). O método apresentou boas taxas de recuperação (92%-105%) e de precisão (desvio padrão relativo (RSD) ≤ 13%), participação satisfatória em ensaios de comparação interlaboratorial (ECI) (Z-score: 0,69 para Crispbread e -0,93 para Biscuit), assim como bons resultados para o ERM-BD272, demonstrando que o método é adequado para a determinação de AA em cereais e derivados. O método foi aplicado a cereais e derivados existentes no mercado, incluindo bolacha Maria, pão de trigo, flocos de milho e bolachas para bebé, todos recolhidos em Lisboa, Portugal. Os resultados de AA das amostras avaliadas, expressos em µg/kg, encontram-se abaixo dos valores legislados pelo Regulamento (EU) 2017/2158. Embora os níveis de acrilamida encontrados cumpram os limites estabelecidos pela União Europeia, é necessária uma monitorização contínua da sua ocorrência, considerando as incertezas ainda presentes sobre os efeitos a longo prazo deste contaminante.The Maillard reaction, responsible for food color, flavor, and aroma, also produces harmful substances such as acrylamide (AA). This unsaturated amide is formed when carbohydrate-rich foods such as bread, potatoes, and coffee are cooked at high temperatures and low humidity. The European Union has classified AA as carcinogenic (Category 1B), mutagenic (Category 1B), and toxic for reproduction (Category 2). The present study aims to validate a method to determine AA in cereals and cereal-based products and investigate its presence in different food items. Ultra-performance liquid chromatography coupled to mass spectrometry (UPLC-MS/MS) with positive electrospray ionization (ESI+ ) was used to detect and quantify AA. The method performance was validated using international external quality control tests such as proficiency tests (FAPAS) and a certified reference material (ERM-BD272). Parameters such as linearity, limit of detection (LD), limit of quantification (LQ), precision, accuracy and uncertainty were evaluated. The LD and LQ were 0.40 µg/L and 1.22 µg/L, respectively, in compliance with Regulation (EU) 2017/2158. The calibration curve showed linearity with an R2 greater than 0.995. The method showed suitable recovery rates (92%-105%) and precision (RSD ≤ 13%), satisfactory participation in interlaboratory comparison (ECI) assays (Z-score: 0.69 for Crispbread and -0.93 for Biscuit) and good results for the ERM-BD272, demonstrating that the method is suitable for the determination of AA in cereals and cereal-based products. The method was applied to commercially available products, including Maria biscuits, wheat bread, corn flakes, and baby biscuits collected in Lisbon, Portugal. The AA results of the evaluated samples, expressed in µg/kg, are below the values legislated by the Commission Regulation (EU) 2017/2158. Although the acrylamide levels found comply with the limits established by the European Union, continuous monitoring of its occurrence is necessary, considering the remaining uncertainties about the long-term effects of this contaminant
Infographic - Familial Hypercholesterolemia 1999-2024
No full textInfográfico disponível em português e inglês.Infográfico desenvolvido no âmbito do Estudo Português de Hipercolesterolemia Familiar, que divulga os dados de Hipercolesterolemia Familiar entre 1999-2024. Coordenado e desenvolvido pelo INSA desde 1999, com a colaboração de vários clínicos de todo o país, este estudo permite identificar a causa genética da hipercolesterolemia (níveis de colesterol elevado desde o nascimento) numa família, para, com diagnóstico precoce e tratamento adequado, reduzir o seu risco cardiovascular.População residente em Portugal com diagnóstico clínico de FH, entre 1999-2024. Dados atualizados a 31-12-2024
Addressing childhood obesity through the lens of Sustainable Development Goal 3 – Good Health and Well-Being: the contribution of the WHO Collaborating Center for Nutrition and Childhood Obesity
No full textA obesidade infantil constitui um dos maiores desafios de saúde pública do século XXI e representa uma ameaça significativa para o cumprimento do Objetivo de Desenvolvimento Sustentável 3 (ODS 3) – Saúde e Bem-Estar, definido pela Agenda 2030 das Nações Unidas.
Este artigo analisa criticamente a relação entre a obesidade infantil e o ODS3, com especial enfoque no papel desempenhado pelo Instituto Nacional de Saúde Doutor Ricardo Jorge (INSA), enquanto Centro Colaborativo da Organização Mundial da Saúde (OMS) para Nutrição e Obesidade Infantil (CCOMS).
Foi realizada uma revisão da literatura científica publicada entre 2020 e 2025, tendo sido identificadas 379 publicações das quais 19 artigos científicos sujeitos a arbitragem por pares foram incluídos na análise final. Seis estudos forneceram evidência direta sobre a relação entre obesidade infantil e o ODS 3, com particular ênfase na meta 3.4, evidenciando a obesidade infantil como fator determinante nas doenças não transmissíveis sublinhando a relevância de dados epidemiológicos e reforçando a necessidade de estratégias intersetoriais e prevenção e promoção da saúde.
Os resultados destacaram ainda a escassez de literatura abrangente que articule soluções sustentáveis para a obesidade infantil em consonância com as metas do ODS 3. O CCOMS enquanto centro de vigilância nutricional infantil (com destaque para o estudo “Childhood Obesity Surveillance Initiative” (COSI) da OMS Europa), pelo seu apoio técnico e ação multissetorial e participação ativa na investigação e inovação científica, tem vindo a reforçar substancialmente o progresso em direção às metas do ODS 3. Em Portugal, os dados recentes do COSI revelam prevalências preocupantes de excesso de peso (31,9%) e obesidade (13,5%) em crianças, confirmando a urgência de medidas eficazes.
Conclui-se que enfrentar a obesidade infantil é crucial para reduzir desigualdades em saúde e avançar no cumprimento do ODS 3, exigindo colaboração internacional e nacional, políticas públicas integradas e intervenções baseadas em evidência científica.Childhood obesity is one of the most pressing public health challenges of the 21st century and poses a major threat to the achievement of Sustainable Development Goal 3 (SDG 3) – Good Health and Wel l-being, as established by the United Nations 2030 Agenda.
This article critically examines the relationship between childhood obesity and SDG 3, with particular emphasis on the role of the National Institute of Health Dr. Ricardo Jorge (INSA), as a World Health Organization (WHO) Collaborating Center for Nutrition and Childhood Obesity (WHOCC).
A literature review of scientific studies published between 2020 and 2025, identified 379 publications, of which 19 peer-reviewed articles were included in the final analysis. Six studies provided direct evidence on the relationship between childhood obesity and the SDG 3, with particular focus on Target 3.4 which consistently highlighted childhood obesity as a key determinant of the global burden of non-communicable diseases (NCDs), under lining the relevance of epidemiological data, and reinforcing the need of intersectoral prevention strategies and health promotion.
Moreover, the findings revealed a lack of comprehensive literature addressing sustainable approaches to childhood obesity aligned with the targets of SDG 3. The WHOCC as a center for nutritional surveillance (notably through the WHO European Childhood Obesity Surveillance Initiative (COSI) study), through its technical suppor t, multisectoral engagement, capacity building, and commitment to research and scientific innovation, WHOCC has substantially strengthened progress towards the achievement of SDG 3. In Por tugal, recent COSI data revealed alarming prevalence of overweight (31.9%) and obesity (13.5%) among children, reinforcing the urgent need for ef fective and evidence-based interventions.
In conclusion, tackling childhood obesi ty is essential to reduce health inequalities and for the advancing progress towards SDG 3. This requires international and national collaboration, integrated public health policies, and sustained investment in evidence-based inter ventions to secure healthier futures for the next generatio
Sitosterolemia In iberoamerican countries: 16 new cases and phenotype genotype analysis
No full textBackground: Sitosterolemia is a rare autosomal recessive lipid disorder caused by biallelic pathogenic variants in ABCG5 or ABCG8 genes. It is characterized by elevated plasma plant sterol concentrations, xanthomas, and an increased risk of premature cardiovascular disease. As happens with familial hypercholesterolemia (FH), sitosterolemia is subdiagnosed and is frequently confounded with FH, resulting in inappropriate management. This study aims to describe newly identified cases across Iberoamerican countries and to highlight the need for improved diagnostic strategies.
Methods: We report 16 cases of molecularly confirmed sitosterolemia from 5 Iberoamerican countries (Argentina, Mexico, Portugal, Spain, and Uruguay), including 12 index cases and 4 relatives identified by cascade screening. Clinical, biochemical, and molecular data were collected and analyzed. β-sitosterol levels were measured when possible, and variant classification followed American College of Medical Genetics and Genomics (ACMG) guidelines with disease-specific adaptations.
Results: Fifteen individuals had biallelic variants in ABCG8 and 1 had a homozygous frameshift variant in ABCG5. Ten distinct ABCG8 variants were identified, including 7 nonsense and 3 missense variants. Xanthomas were observed in 56% of cases. Most cases were initially diagnosed as FH, with a diagnostic delay of up to 30 years. Treatment with ezetimibe, alone or combined with statins, led to biochemical and clinical improvement, including xanthoma regression in some cases.
Conclusion: Sitosterolemia remains underdiagnosed due to lack of systematic screening and clinical overlap with FH. Our findings highlight the importance of including ABCG5/8 in genetic testing panels and of recognizing clinical clues for early diagnosis, enabling targeted treatment and prevention of adverse outcomes. Adapted ACMG variant classification improves interpretability for ABCG5/8-related sitosterolemia.Highlights: -Sitosterolemia is a rare autosomal recessive lipid disorder caused by biallelic variants in the ABCG5/8 genes; - We report 16 cases from 5 Iberoamerican countries (12 index cases and 4 relatives); 15 had biallelic ABCG8 variants and 1 had a biallelic identical ABCG5 variant; - Sitosterolemia remains underdiagnosed due to the lack of systematic screening for inherited dyslipidemias in at-risk individuals; - We propose for the first time ACMG-adapted variant classification criteria for ABCG5/8 genes; - Timely genetic diagnosis allows appropriate treatment, preventing complications such as premature cardiovascular disease.MA-R received a Postdoctoral Junior Leader - IN- COMING Fellowship from “la Caixa”Foundation (ID: 100010434) and from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska Curie grant agreement No. 847648 (fellow- ship code: LCF/BQ/PI21/11830009). One of the Spanish cases was studied in NAGENCOL project (0011-1411-2019- 000049 - Estrategia navarra en medicina genómica aplicada a hipercolesterolemia) funded by the Government of Navarra (GEMA call 2019-2021)
Estudo da qualidade microbiológica de queijos da Beira Baixa fabricados com leite cru
No full textDissertação de Mestrado em Biologia Humana e Ambiente, apresentada à Faculdade de Ciência da Universidade de Lisboa, 2023.Dissertação orientada por Doutora Rita Maria Cruz de Campos Batista, Instituto Nacional de Saúde Doutor Ricardo Jorge e Prof. Doutora Lélia Mariana Marcão Chambel, Faculdade de Ciência da Universidade de Lisboa.203523946Os queijos fabricados com leite cru fazem parte da cultura gastronómica portuguesa, sendo valorizados
produtos de elevada qualidade microbiológica para garantir a segurança dos consumidores.
Neste estudo avaliou-se a deteção e/ou contagem de Escherichia coli patogénica, Staphylococcus spp.
coagulase positiva (CP), Salmonella spp. e Listeria monocytogenes, e de microrganismos indicadores
de higiene (E. coli não patogénica e outras Listeria spp.) em 98 queijos da Beira Baixa fabricados com
leite cru, e realizou-se a caracterização fenotípica e genotípica de isolados.
Foram utilizados métodos baseados nas normas ISO e métodos para quantificação, deteção e
identificação de bactérias (TEMPO®, VIDAS® e VITEK®, respetivamente). Fenotipicamente foram
efetuados testes de suscetibilidade a antimicrobianos (E. coli e Salmonella spp.), testes da atividade
hemolítica (E. coli) e teste de serotipagem por aglutinação (Salmonella spp.). Genotipicamente
realizaram-se ensaios de PCR multiplex (pesquisa de genes específicos de E. coli patogénica intestinal)
e sequenciação total do genoma (E. coli, Listeria spp. e Salmonella spp.), com deteção de genes de
virulência e de resistência a antimicrobianos (E. coli e Salmonella spp.), bem como análise de clusters
(E. coli e Listeria spp.).
Detetou-se a presença de E. coli, Staphylococcus spp. CP, L. monocytogenes, Listeria innocua e
Salmonella spp. em 73,5%, 63,3%, 4,1%, 4,1% e 1,0% das amostras, respetivamente. Não foram
detetadas enterotoxinas estafilocócicas. Foram detetados três isolados de E. coli patogénica
extraintestinal (ExPEC), um hemolítico e dois resistentes a múltiplos antimicrobianos (Ampicilina,
Cloranfenicol, Sulfametoxazol, Tetraciclina), ST (sequence type) 14755, ST155 e ST362,
respetivamente; um isolado de Salmonella Duisburg (ST4046) suscetível aos antimicrobianos testados
e com dois genes associados a resistências; quatro isolados de L. monocytogenes (ST1, ST5, ST7) e
quatro isolados de L. innocua (ST492, ST603).
A contaminação encontrada poderá estar relacionada com a não adesão às boas práticas de higiene e
segurança dos alimentos ao longo do processo de fabrico.Cheeses made from raw milk are part of Portuguese gastronomic culture, with products of high microbiological quality being valued to guarantee consumer safety.
In this study, the detection and/or count of pathogenic Escherichia coli, coagulase-positive (CP) Staphylococcus spp., Salmonella spp. and Listeria monocytogenes, as well as hygiene indicator microorganisms (non-pathogenic E. coli and other Listeria spp.) in 98 raw milk cheeses from Beira
Baixa region, and phenotypic and genotypic characterization of isolates was carried out.
Methods based on ISO standards and methods for quantification, detection and identification of bacteria
(TEMPO®, VIDAS® and VITEK®, respectively) were used. Phenotypically, antimicrobial susceptibility
tests (E. coli and Salmonella spp.), hemolytic activity tests (E. coli) and agglutination serotyping test
(Salmonella spp.) were carried out. Genotypically, multiplex PCR assays (search for specific genes of
intestinal pathogenic E. coli) and total genome sequencing (E. coli, Listeria spp. and Salmonella spp.)
were carried out, with detection of virulence and antimicrobial resistance genes (E. coli and Salmonella
spp.), as well as cluster analysis (E. coli and Listeria spp.).
The presence of E. coli, CP Staphylococcus spp., L. monocytogenes, Listeria innocua and Salmonella
spp. was detected in 73.5%, 63.3%, 4.1%, 4.1% and 1.0% of the samples, respectively. No
staphylococcal enterotoxins were detected. Three isolates of extraintestinal pathogenic E. coli (ExPEC)
were detected, one hemolytic and two resistant to multiple antimicrobials (Ampicillin,
Chloramphenicol, Sulfamethoxazole, Tetracycline), ST (sequence type) 14755, ST155 and ST362,
respectively; an isolate of Salmonella Duisburg (ST4046) susceptible to the antimicrobials tested and
with two genes associated with resistance; four isolates of L. monocytogenes (ST1, ST5, ST7) and four
isolates of L. innocua (ST492, ST603).N/
Translational regulation mediated by upstream open reading frames im PERK mRNA
No full textGenome-wide studies pointed out translation as a major regulator of gene expression, being a key post-transcriptional mechanism by which cells rapidly change their gene expression pattern in response to diverse stimuli. Upstream open reading frames (uORFs) are examples of cis-acting elements that can regulate translation initiation. A uORF is defined as a coding sequence located within the 5’untranslated region (5’UTR) of an mRNA and is typically considered a repressor of main ORF (mORF) translation. This can be due to the recognition of the uORF start codon by the preinitiation complex. In this case, when the translating ribosome encounters the uORF stop codon, the translation machinery disassembles, avoiding mORF translation if the ribosome cannot reinitiate at the main start codon. ATF4, CHOP and GADD34 are stress-response proteins encoded by uORF-harboring transcripts with translation repression activity, which is responsible for maintaining a low expression of these proteins in normal conditions. However, when ER stress occurs, the unfolded protein response (UPR) is activated and eIF2α is phosphorylated by PERK. In these cases, the availability of the preinitiation complex is reduced, favoring translation of the mORFs. The stress-response proteins are therefore up regulated, triggering a cascade of events aiming stress resolution and cell survival.
In this work we intended to determine if PERK is regulated at the translational level in normal and ER stress conditions. We have validated the annotated sequence of PERK 5’UTR using 5’RACE, and we have selected uORFs based on ribosome profiling data already available. Then, we have cloned the 5’UTR into a reporter plasmid, in frame with firefly luciferase ORF. Using site-directed mutagenesis, we have made constructs with mutated uORFs to evaluate their impact in translation efficiency. Our data suggest that the uORFs have a repressive effect in mORF translation, and we are now dissecting the mechanisms that drive this regulation.Partially supported by UID/MULTI/04046/2013 center grant from FCT to BioISI. RF is recipient of a fellowship from BioSys PhD programme
(SFRH/BD/114392/2016) from FCT.info:eu-repo/semantics/publishedVersio
The interplay between nonsense-mediated mRNA decay (NMD) and the unfolded protein response (UPR) in myocardial infarction
No full textMany genome-wide studies pointed out translation as a major regulator of gene expression, being a key post-transcriptional mechanism by which cells rapidly change their gene expression pattern in response to diverse stimuli. There are several cis-acting elements that can be involved in the regulation of translation initiation, including upstream open reading frames (uORFs). A uORF is defined as a coding sequence that is located within the 5’ untranslated region (5’UTR) of a transcript, and it is typically considered an inhibitor of downstream translation initiation at the main ORF (mORF). This can be due to the recognition of the uORF start codon by the preinitiation complex. In this case, when the translating ribosome encounters the stop codon of the uORF, the translation machinery disassembles, a fact that can avoid translation of the mORF if the ribosome cannot reinitiate at the main start codon. ATF4, CHOP and GADD34 are stress-response proteins encoded by uORF-harboring transcripts with translation repression activity, which is responsible for maintaining a low expression of these proteins in normal conditions. However, when ER stress occurs, the unfolded protein response (UPR) is activated and eIF2α is phosphorylated by PERK. In these cases, the availability of the preinitiation complex is reduced, favoring translation of the mORFs. The stress-response proteins are therefore up regulated, triggering a cascade of events aiming stress resolution and cell survival.
Given that many factors of the PERK-pathway of the UPR are regulated by uORFs, in this work we intended to determine if PERK is also regulated at the translational level. We have started by validating the annotated sequence of PERK 5’UTR using 5’RACE. Then, we have selected uORFs based on ribosome profiling data already available. To study the role of these uORFs in translational regulation of PERK, we have cloned its 5’UTR into a reporter plasmid, in frame with firefly luciferase ORF. Using site-directed mutagenesis, we have made constructs with mutated uORFs to evaluate their impact in translation efficiency. Our data, suggests that the uORFs have a repressive effect in mORF translation, and we are now dissecting the mechanisms that drive this regulation, in normal and ER stress conditions.This project is partially funded by Fundação para a Ciência e Tecnologia (UID/Multi/04046/2013 to BioISI from
FCT/MCTES/PIDDAC), and also by National Institute of Health Dr. Ricardo Jorge. R.Q.F. is recipient of a fellowship from BioSys PhD programme (Ref SFRH/BDXXX/201Y) from FCT (Portugal).N/
Regulation of IRES-mediated translation in p53
No full textThe tumor microenvironment is characterized by several stresses impairing canonical translation. However, specific mRNAs harbouring internal ribosome entry sites (IRES), such as several tumour suppressors and oncogenes, can overcome this impairment. The tumor suppressor TP53 gene, an important transcription factor that ensures cellular homeostasis, is frequently mutated in human cancers. Over the years, several p53 isoforms have been identified, which in some cases result from alternative initiation of translation regulated by an IRES. Recently, we have associated mutant p53 “gain-of-function” cancer phenotype, such as enhanced cell survival, invasion, proliferation, and adhesion, with the expression of higher levels of shorter p53 isoforms, such as Δ160p53 isoform.1 Here, we used a bicistronic system containing two reporter luciferases (renilla luciferase and firefly luciferase) to assess IRES-mediated translation. Several p53 mRNA elements were tested in this system and, interestingly, we have found an inhibitory element of IRES-mediated translation. Overall, IRES-regulated translation in malignant cells is used to translate specific proteins that promote cancer progression. Thus, inhibiting translation of oncogenes via IRES could prevent the formation of tumor cells and their adaptation to unfavourable conditions in the tumor microenvironment.
1. Candeias, M. M., Hagiwara, M. & Matsuda, M. Cancer‐specific mutations in p53 induce the translation of Δ160p53 promoting tumorigenesis. EMBO Rep. 17, 1542–1551 (2016).The project is funded by FCT grant PTDC/MED-ONC/32048/2017N/