An ERK1/2-driven RNA-binding switch in nucleolin drives ribosome biogenesis and pancreatic tumorigenesis downstream of RAS oncogene

Oncogenic RAS signaling reprograms gene expression through both transcriptional and post‐transcriptional mechanisms. While transcriptional regulation downstream of RAS is relatively well characterized, how RAS post‐transcriptionally modulates gene expression to promote malignancy remains largely unclear. Using quantitative RNA interactome capture analysis, we here reveal that oncogenic RAS signaling reshapes the RNA‐bound proteomic landscape of pancreatic cancer cells, with a network of nuclear proteins centered around nucleolin displaying enhanced RNA‐binding activity. We show that nucleolin is phosphorylated downstream of RAS, which increases its binding to pre‐ribosomal RNA (rRNA), boosts rRNA production, and promotes ribosome biogenesis. This nucleolin‐dependent enhancement of ribosome biogenesis is crucial for RAS‐induced pancreatic cancer cell proliferation and can be targeted therapeutically to inhibit tumor growth. Our results reveal that oncogenic RAS signaling drives ribosome biogenesis by regulating the RNA‐binding activity of nucleolin and highlight a crucial role for this mechanism in RAS‐mediated tumorigenesis

Subcellular mRNA Localization Regulates Ribosome Biogenesis in Migrating Cells

Translation of ribosomal protein-coding mRNAs (RP-mRNAs) constitutes a key step in ribosome biogenesis, but the mechanisms that modulate RP-mRNA translation in coordination with other cellular processes are poorly defined. Here, we show that subcellular localization of RP-mRNAs acts as a key regulator of their translation during cell migration. As cells migrate into their surroundings, RP-mRNAs localize to the actin-rich cell protrusions. This localization is mediated by La-related protein 6 (LARP6), an RNA-binding protein that is enriched in protrusions. Protrusions act as hotspots of translation for RP-mRNAs, enhancing RP synthesis, ribosome biogenesis, and the overall protein synthesis in migratory cells. In human breast carcinomas, epithelial-to-mesenchymal transition (EMT) upregulates LARP6 expression to enhance protein synthesis and support invasive growth. Our findings reveal LARP6-mediated mRNA localization as a key regulator of ribosome biogenesis during cell migration and demonstrate a role for this process in cancer progression downstream of EMT

French DNCG management control versus UEFA Financial Fair Play: a divergent conception of financial regulation objectives

© 2017 Informa UK Limited, trading as Taylor & Francis Group. The French Football Federation was the first football governing body to put in place, in 1990, a financial regulation system. It might be expected that UEFA’s Financial Fair Play (FFP) system established in 2010 would be similar to French DNCG (National Direction for Management Control) regulations. However, while FFP is concerned with profitability, DNCG is focused on solvency. Hence, a French club may be loss-making and not compliant with FFP, while at the same time being solvent in accordance with DNCG rules. Our research confirms that most French clubs do not conform to FFP rules. As such, it provides further evidence that DNCG has not prevented poor financial management within French clubs. The coexistence of DNCG and FFP– or any other domestic financial regulation and FFP –may result in disparities between domestic clubs. As a consequence, there should be consistent financial regulation in all European leagues

RBMS1 Suppresses Colon Cancer Metastasis through Targeted Stabilization of Its mRNA Regulon

Identifying master regulators that drive pathologic gene expression is a key challenge in precision oncology. Here, we have developed an analytic framework, named PRADA, that identifies oncogenic RNA-binding proteins through the systematic detection of coordinated changes in their target regulons. Application of this approach to data collected from clinical samples, patient-derived xenografts, and cell line models of colon cancer metastasis revealed the RNA-binding protein RBMS1 as a suppressor of colon cancer progression. We observed that silencing RBMS1 results in increased metastatic capacity in xenograft mouse models, and that restoring its expression blunts metastatic liver colonization. We have found that RBMS1 functions as a posttranscriptional regulator of RNA stability by directly binding its target mRNAs. Together, our findings establish a role for RBMS1 as a previously unknown regulator of RNA stability and as a suppressor of colon cancer metastasis with clinical utility for risk stratification of patients. SIGNIFICANCE: By applying a new analytic approach to transcriptomic data from clinical samples and models of colon cancer progression, we have identified RBMS1 as a suppressor of metastasis and as a post-transcriptional regulator of RNA stability. Notably, RBMS1 silencing and downregulation of its targets are negatively associated with patient survival.See related commentary by Carter, p. 1261.This article is highlighted in the In This Issue feature, p. 1241

A prometastatic splicing program regulated by SNRPA1 interactions with structured RNA elements

Aberrant alternative splicing is a hallmark of cancer, yet the underlying regulatory programs that control this process remain largely unknown. Here, we report a systematic effort to decipher the RNA structural code that shapes pathological splicing during breast cancer metastasis. We discovered a previously unknown structural splicing enhancer that is enriched near cassette exons with increased inclusion in highly metastatic cells. We show that the spliceosomal protein small nuclear ribonucleoprotein polypeptide A' (SNRPA1) interacts with these enhancers to promote cassette exon inclusion. This interaction enhances metastatic lung colonization and cancer cell invasion, in part through SNRPA1-mediated regulation of PLEC alternative splicing, which can be counteracted by splicing modulating morpholinos. Our findings establish a noncanonical regulatory role for SNRPA1 as a prometastatic splicing enhancer in breast cancer

Condutância estomática em folhas de feijoeiro submetido a diferentes regimes de irrigação Stomatal conductance in leaves of bean plants submitted to different irrigation regimes

O controle estomático é importante propriedade fisiológica por meio da qual as plantas limitam a perda de água, ocasionando reduções na condutância estomática e, geralmente, reduzindo as trocas gasosas como forma de resposta das plantas a diversos fatores, incluindo o estresse hídrico. O objetivo deste trabalho foi determinar a condutância estomática em folhas de feijoeiro submetido a diferentes regimes de irrigação. O experimento foi conduzido no Departamento de Engenharia Rural da Faculdade de Ciências Agrárias e Veterinárias de Jaboticabal - SP. As irrigações nos tratamentos foram determinadas em função do esgotamento de água no solo: T1 - irrigado quando esse atingiu 40% da capacidade de água disponível (CAD); T2 - quando atingiu 60% da CAD; T3 - quando atingiu 80% da CAD, e T4 - não irrigado (irrigado somente para favorecer a emergência das plântulas). As medições de condutância estomática foram realizadas diariamente no campo, nas duas faces da folha, utilizando-se de um porômetro. Em todos os tratamentos, em diversas medições, foi observada redução da condutância estomática em resposta a baixos valores de potencial mátrico e a altos valores de déficit de pressão de vapor e vice-versa. As folhas das plantas do tratamento T4, que foram submetidas a menor disponibilidade hídrica no solo, apresentaram os menores valores de condutância estomática durante os estádios do florescimento e enchimento de grãos.<br>Stomatal control is an important physiological process for plants to reduce water loss. It causes reduction in stomatal conductance and generally in gas exchanges, as a response of several factors including water stress. The objective of this study was to determine the stomatal conductance of bean leaves submitted to different irrigation regimes. Field experiment was conducted at the São Paulo State University, in Jaboticabal, Brazil. Irrigation of the treatments occurred when available water capacity in the soil decreased to 40; 60 and 80% (respectively, treatments T1, T2 and T3), while irrigation in T4 occurred only to assure seedling emergence. Direct measurements of stomatal conductance were taken every day under field conditions in both adaxial and abaxial leaf surfaces using porometer. In all treatments, several measurements showed reduced stomatal conductance in response to low values of matric potential and high values of vapor pressure deficit (DPV) and vice-versa. The lowest values of stomatal conductance of T4 leaves, taken from plants under the most restrictive water supply regime tested in this study, were observed during the period of plant flowering and grain development

Variabilidade sazonal da condutância estomática em um ecossistema de manguezal amazônico e suas relações com variáveis meteorológicas Seasonal variability of the stomatal conductance in Amazonian mangrove ecosystem and their relationships with meteorological variables

No presente trabalho foram estudadas as variações da condutância estomática (g s) para o período chuvoso (março) e seco (agosto) do ano de 2003, e suas relações de dependência com algumas variáveis meteorológicas medidas em um ecossistema de manguezal amazônico. As informações utilizadas foram do projeto ECOBIOMA, parte integrante do Experimento de Grande Escala da Biosfera-Atmosfera da Amazônia (LBA). A g s acompanha a tendência de variação do balanço de radiação, atingindo valores máximos durante o dia e mínimos durante a noite. A condutância apresentou maiores flutuações no período chuvoso, com valor médio de g s = 0,015 m s-¹, porém com magnitudes inferiores as do período seco. Durante a época seca apresentou um valor médio de g s = 0,027 m s-¹, com menor amplitude, variando de 0,010 < g s < 0,042 m s-¹. As variáveis meteorológicas utilizadas para o estabelecimento de relações de dependência com a variabilidade diária de g s foram déficit de umidade específica (&#948;q), déficit de pressão de vapor (DPV), saldo de radiação (Rn) e velocidade do vento (Vv). O DPV apresentou as melhores correlações com a g s sendo o R² = 0,99 em ambos os períodos. Apesar de também ser importante nas trocas gasosas entre a vegetação e a atmosfera, a Vv apresentou a menor influência na variação média da g s, com um R² = 0,44 para época chuvosa e R² =0,51 para o período seco.<br>This work investigated the variations of stomatal conductance (g s) in the rainy and dry seasons and its dependence relations with meteorological variables measured in an Amazonian mangrove ecosystem. Data were originated from the ECOBIOMA project, part of the Large Scale Biosphere-Atmosphere Experiment in Amazon (LBA). Stomatal conductance followed the tendency of the radiation balance variation, reaching maximum values during the day and minimum values at night. The conductance showed greater fluctuations in the rainy season, with mean value of g s = 0.015 m s-¹, however smaller in magnitude than in the dry season. During the dry season, the mean value was g s = 0.027 m s-¹, with lower range, varying between 0.010 and 0.042 m s-¹. The meteorological variables used for establishing the dependence relations with the daily variability of stomatal conductance were the following; specific moisture deficit (&#948;q), vapor pressure deficit (PVD), net radiation (Rn) and wind velocity (Vv). The PVD showed the best correlation with g s, with R² = 0.99 for both periods. In spite of the importance of Vv in the gaseous changes between the vegetation and the atmosphere, it presented the smallest influence in the mean variation of the gs, with R² = 0,44 for the rainy and R² =0,51 for the dry period

Oxidative stress downstream of mTORC1 but not AKT causes a proliferative defect in cancer cells resistant to PI3K inhibition

This work was supported by St Peters Trust and Barts and The London Charity (BLT 297/2249). PRC was supported by BBSRC Grant BB/M006174/1